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DRUG RESISTANCE IN BREAST CANCER

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DRUG RESISTANCE IN BREAST CANCER

ABSTRACT:

Drug resistance is a major challenge to the effective treatment of breast cancer, causing treatment failure and disease progression. There is a variety of molecular mechanisms that lead the development of resistance, such as target mutations, changes in tumor microenvironment, and the attraction of novel signaling pathways. This chapter summarizes the recent advances in understanding of the molecular mechanisms of drug resistance in breast cancer. It will offer a close focus on the novel biomarkers for resistance to systematic therapy, in vitro and in vivo models that help understand resistance and emerging strategies for overcoming resistance and reducing side effects. Recent studies have identified a number of novel genetic and epigenetic alterations that contribute to drug resistance in breast cancer. The identified alterations include mutation in the targeted genes, changes in the expression of drug transporters, and the activation of signaling pathways that promote tumor growth and survival. Active research should, therefore, be targeted at developing new strategies for overcoming drug resistance in breast cancer. Emerging approaches include the use of combination therapies, the development of new targeted therapies, and the inhibition of drug transports.

Keywords: Drug resistance, Molecular mechanisms, Target mutations, Tumor microenvironment

INTRODUCTION:

Picture a scenario where cutting-edge research serves as a beacon of light, guiding us through the labyrinthine pathways of cellular resistance. Imagine a world in which the strategies employed to sensitize breast cancer cells to treatment become threads that unravel the enigma of drug resistance, paving the way for breakthroughs that could change the course of countless lives. As we embark on this exploration, we will immerse into the heart of molecular intricacies, decoding the language of genes, proteins, and signaling pathways that orchestrate the destiny of cancer cells.

Currently, drug resistance has become a primary obstacle in cancer treatment. Despite advances in targeted therapy and immunotherapy, many tumors eventually become resistant to treatment [1, 2]. These factors include the development of new mutations, changes in the tumor microenvironment, and activation of novel signaling pathways [3, 4]. The current chapter reviews recent advances in understanding the molecular mechanisms underlying drug resistance in breast cancer [5]. In response, this study discusses novel biomarkers for resistance to systematic therapy, in vitro and in vivo models helpful for understanding drug resistance, and emerging strategies for overcoming resistance and reducing side effects [6]. This field's current state of research is rapidly evolving [7]. Consistently increasing evidence has indicated progress in understanding of the complex molecular mechanisms that contribute to drug resistance. However, much remains to be revealed; thus, further research is needed to develop new and effective strategies for overcoming resistance [8, 9]. Nonetheless, there is controversy and a diverging hypothesis in the field of drug resistance in breast cancer. For instance, there is some debate regarding the role of tumor heterogeneity in drug resistance [10]. Marusyk et al. showed that tumors that are more heterogeneous are more likely to become resistant to treatment [10]. Furthermore, growing evidence has shown that the tumor microenvironment can play a role in drug resistance. For example, some studies have shown that the presence of immune cells can promote drug resistance, whereas others have shown that the presence of fibroblasts can promote drug resistance [11]. The main aim of this chapter was to review the recent advances in understanding the molecular mechanisms underlying drug resistance in breast cancer [12]. Developing new strategies for overcoming drug resistance in breast cancer is a major area of active research [12]. The primary mechanisms established and utilized include combination therapies, the development of new targeted therapies, and the inhibition of drug transporters.

CELL LINES AND CULTURE CONDITIONS:

Breast cancer is the leading cause of death worldwide. Breast cancer can be detected and treated using several methods. However, the testing process requires expertise and innovation to ensure that tumors are identified and treated. In this chapter, we identified different cell lines that facilitate the effective detection of the primary cause of drug resistance in treatment measures. The cell lines identified in this chapter were MDA-MB-231 and BT-474 cells. Cells are cultured in DMEM/F12 supplemented with 10% FBS, 1% penicillin/streptomycin, and 1% I-glutamine. Evidence from this study reveals that MDA-MB-231 is a commonly used breast cancer cell line, especially by medical researchers [13]. In testing these hypotheses, PDBs deposits were scattered at different points, including the cytoplasm and across the walls of the membrane. Evidence from TEM micrographs of the treatment showed both apoptotic and necrotic death, each with specific features [14]. Thus, various cell culture techniques have been developed based on the modeling of cancer structures in 3D cell cultures.

Heterogeneity in cell lines permits a comprehensive approach to evaluating breast cancer cell lines to get a clear understanding of drug resistance mechanisms. In the case of the T-47D cell line, it has been used in drug resistance research to provide more information regarding hormonal therapies for breast cancer [15]. The application of various cell lines is vital since several subtypes of breast cancer might respond to various treatments differently, and the evaluation of several cell lines helps in tailoring therapeutic approaches to particular patients [16]. This study revealed that culturing cell lines in a controlled environment is important for reproducibility and attested procedure. The DMEM/F12 supplemented with 10% FBS, 1% penicillin/streptomycin, and 1% I-glutamine has shown to be an effective culture medium for the cell lines and conditions [17]. The growth of 3D cell culture strategies has changed the field by giving a more physiologically significant platform for the assessment of drug resistance [18]. Such models resemble the environment of a breast tumor and give an exact representation of drug response, hence bridging the gap between the traditional monolayer and in vivo cultures.

Figure 11.1. Cell lines to study changes leading to resistance mechanism

Elucidating the Mechanism of Drug Resistance in Breast Cancer:

To elucidate the mechanism of drug resistance in breast cancer, a complex interplay between various factors is required. These factors include targeted mutations, tumor microenvironment, undiscovered genes, and signaling pathways.

Targeted Mutation:

Mutations in specific genes can lead to the development of drug resistance in breast cancer. One well-known example is a mutation in the HER2 gene, which can result in resistance to HER2-targeted therapies such as trastuzumab (Herceptin) [19]. Additionally, mutations in genes, such as TP53 (p53) and BRCA1/2, can affect DNA repair mechanisms and promote resistance to chemotherapy [20]. Targeted therapies may become less effective as cancer cells evolve to bypass the targeted pathways through mutations.

Tumor Microenvironment:

The tumor microenvironment (TME) plays a crucial role in drug resistance. Factors within the TME, such as immune cells, stromal cells, and extracellular matrix components, can influence cancer cell behavior and response to treatment [21]. TME components secrete factors that promote survival and growth of drug-resistant cancer cells. Hypoxia (low oxygen levels) within the TME can activate the survival pathways contributing to resistance.

Undiscovered Genes:

There are likely undiscovered genes that contribute to drug resistance in breast cancer. Advances in genomics and techniques such as CRISPR/Cas9 screening have helped researchers identify novel genes that play a role in resistance mechanisms. These genes may be involved in pathways that are not yet well understood or that are not traditionally associated with drug resistance.

Signaling Pathways:

Various signaling pathways have been implicated in drug resistance. For example, the PI3K/AKT/mTOR pathway is often dysregulated in breast cancer and contributes to drug resistance by promoting cell survival and proliferation. The MAPK/ERK pathway is another important pathway that can influence drug sensitivity [21]. Targeted therapies may initially inhibit these pathways; however, cancer cells may develop resistance by activating alternative or compensatory pathways.

PROMISING DRUG DELIVERY SYSTEM THAT CAN ENHANCE THE SENSITIVITY OF ANTI-BREAST CANCER AGENTS TO VARIOUS TUMORS:

Nanoparticle-based drug delivery is a promising drug delivery system that can enhance the sensitivity of breast cancer agents to various tumors. Nanoparticles are tiny particles ranging from 1-100 nanometers that offer several advantages for delivering anticancer drugs.

Targeted Delivery:

Nanoparticles can be designed to specifically target cancer cells or the tumor microenvironment, thereby minimizing damage to healthy cells and tissues. Functionalization of nanoparticles with targeting ligands (such as antibodies or peptides) allows them to selectively bind to cancer cells [21].

Enhanced Permeability and Retention (EPR) Effect:

Nanoparticles can exploit the EPR effect, which is the tendency of tumors to have leaky blood vessels and impaired lymphatic drainage [21]. This phenomenon allows nanoparticles to accumulate preferentially in tumor tissues, increasing the drug concentration at the tumor site.

Sustained Release:

Nanoparticles can encapsulate drugs and release them in a controlled and sustained manner. This can lead to prolonged drug exposure in tumors, enhanced drug efficacy, and reduced side effects.

Multidrug Loading:

Nanoparticles can carry multiple drugs or therapeutic agents simultaneously, allowing combination therapies to target multiple pathways involved in drug resistance.

Overcoming Efflux Pumps:

Nanoparticles can help overcome the drug efflux pumps that cancer cells often use to expel drugs [22]. Encapsulating drugs within nanoparticles makes them less susceptible to efflux, leading to increased intracellular drug accumulation.

Reduced Systemic Toxicity:

By specifically delivering drugs to tumor sites, nanoparticle-based delivery systems can reduce the exposure of healthy tissues to toxic anticancer agents, thereby minimizing the systemic adverse reaction.

Personalized Medicine:

Nanoparticles can be tailored to individual patients based on their specific tumor characteristics and drug responses, enabling a personalized treatment approach. Examples of nanoparticle-based drug delivery systems that have shown promise in enhancing the sensitivity of anti-breast cancer agents include liposomes, polymeric nanoparticles, micelles, dendrimers, and nanodiamonds [22]. These systems have been used to deliver chemotherapeutic drugs, targeted therapies, and nucleic acid-based therapies to breast cancer cells.

Figure No. 11.2. Cancer cells showing resistance to cytotoxic anti-cancer drugs.

Strategies That Can Improve Patient Care during Bio chemotherapeutic Treatments:

During biochemotherapy, which combines chemotherapy and immunotherapy, patient care requires a comprehensive and patient-centered approach. Patients' quality of life is strongly impacted by their chosen treatment strategy for breast cancer. Fighting spirit, positive reframing, helplessness or hopelessness, and worried obsession are only a few of the coping strategies for cancer that have been documented. A patient who adopts a positive outlook is inspired to see their condition as a challenge and take steps to overcome it. Destructive strategies take the form of feelings of helplessness, anxiety, and a propensity to interpret any symptom as a sign of health deterioration, while positive redefinition enables the patient to find hope and fulfillment in life while maintaining full awareness of the severity of their illness. The latter may increase the negative consequences of mastectomy, particularly the symptoms associated with the breast and the arm, and it may encourage a submissive attitude toward the condition. Therefore, a system of strategic measures must be included to ensure its effectiveness and efficiency.

Multidisciplinary Team Collaboration:

The multidisciplinary team of oncologists, nurses, pharmacists, nutritionists, social workers, and psychologists [22]. Collaborative care ensures that patients receive holistic support to address their medical, emotional, and practical needs.

Patient Education:

Provide clear and thorough education about the treatment plan, potential side effects, and how to manage them. Empower patients with the knowledge to make informed decisions and manage treatment-related challenges effectively.

Individualized Treatment Plans:

Tailor treatment plans for each patients medical history, tumor characteristics, and personal preferences [23]. Personalized treatment approaches can lead to better outcomes and patient satisfaction.

Proactive Symptom Management:

Monitor patients closely for side effects and symptoms, and implement proactive measures to manage and mitigate these effects. Prompt intervention can prevent complications and improve treatment adherence.

Supportive Care Interventions:

Nutritional support: Provides guidance on maintaining a balanced diet to support the immune system and manage treatment-related nutritional challenges.

Pain Management: Develop effective pain management strategies to enhance patient comfort and QoLPsychosocial support: Offered counseling, support groups, and therapy services to address emotional and psychological well-being.

Optimized Chemotherapy Administration:

Dose Adjustment: Adjust chemotherapy doses based on individual patient characteristics and tolerability to minimize toxicity while maintaining treatment effectiveness.

Infusion Timing: Strategically schedule chemotherapy and immunotherapy infusions to minimize overlapping side effects and optimize patient recovery.

Patient-Centered Communication:

Open Dialogue: Foster open communication between healthcare providers and patients, allowing them to express concerns, ask questions, and participate actively in their care [23].

Shared decision-making: Involves patients in treatment decisions, considering their preferences, values, and goals.

SMALL MOLECULE COMPOUNDS THAT ARE EFFECTIVE AGAINST DRUG-RESISTANT BREAST TUMORS, BIOMARKERS, OF CHEMOTHERAPY RESISTANCE IN BREAST CANCER PATIENTS:

Several molecular compounds have shown promise in targeting drug-resistant breast tumors. Additionally, researchers have identified various biomarkers associated with chemotherapy resistance in breast cancer patients. Below is a discussion of these molecular compounds:

Small Molecule Compounds:

Table 1: Small Molecule and Compounds

LapatinibLapatinib is a tyrosine kinase inhibitor that targets both the HER2 and EGFR receptors. It has shown effectiveness against HER2-positive breast tumors that have developed resistance to other HER2-targeted therapies [24].

Palbociclib, Ribociclib, and AbemaciclibThese CDK4/6 inhibitors have been effective in targeting hormone receptor-positive breast cancer cells, including those resistant to endocrine therapy.

EverolimusIs an mTOR inhibitor that has shown promise in overcoming resistance to hormone therapy in certain breast cancer cases.

T-DM1 (TrastuzumabEmtansine) T-DM1 is an antibody-drug conjugate that combines trastuzumab with a chemotherapeutic drug. It has demonstrated efficacy in HER2-positive breast cancers resistant to trastuzumab [24].

PARP Inhibitors (Olaparib, Talazoparib) PARP inhibitors effectively treat breast cancers with BRCA mutations, which are often associated with increased drug resistance.

Biomarkers of Chemotherapy Resistance:

Table 2: Biomarkers of Chemotherapy Resistance:

P-glycoprotein (P-gp) Overexpression of P-gp, a drug efflux pump, reduces the intracellular concentration of chemotherapeutic drugs in cancer cells, leading to drug resistance.

BRCA Mutations Breast cancer patients with mutations in BRCA genes can be more resistant to certain types of chemotherapy but may respond well to PARP inhibitors [24].

TP53 Mutations Breast cancer patients with mutations in BRCA genes can be more resistant to certain types of chemotherapy but may respond well to PARP inhibitors [24].

ERCC1 Expression High expression of ERCC1, a DNA repair enzyme, is associated with resistance to platinum-based chemotherapeutic agents.

Ki-67 High levels of the Ki-67 protein, a cell proliferation marker, have been linked to resistance to hormone therapy and chemotherapy.

HER2 Expression In HER2-positive breast cancer, decreased HER2 expression is associated with resistance to HER2-targeted therapies.

MicroRNA Expression Altered expression of specific microRNAs has correlated with chemotherapy resistance and could serve as predictive biomarkers [24].

DNA Repair Pathway Genes Alterations in DNA repair pathway genes, such as those involved in homologous recombination repair, can impact sensitivity to DNA-damaging chemotherapy agents.

Mechanism of Drug Resistance in Breast Cancer:Literature reviews revealed numerous molecular mechanisms contributing to drug resistance in breast cancer [25, 26]. Substantial evidence supports the role of genetic alterations, including somatic mutations, gene amplification, and deletions, as the major determinants of resistance to targeted therapies. Mutations in genes encoding drug targets [26]. The encoded drug targets include HER2, ER, and PIK3CA, which are frequently observed in resistant tumors, leading to decreased drug binding or activation of alternate signaling pathways [26]. From this perspective, it is evident that drug resistance in cancer cells is mediated by either acquired or de novo mechanisms. Table 3: Mechanism of Drug Resistance in Breast Cancer.

Mechanism of Drug Resistance in Breast Cancer

Mechanism Description

Genetic Alterations Some mutations, in like gene-encoding drug targets such as ER, PIK3CA and HER2 are evident.

The primary causes of drug resistance include gene amplification, deletions and somatic mutations.

Acquired Resistance It involves alterations in drug target genes. Drug resistance can develop as a result of prolonged exposure to treatments, causing genetic changes.

Tumor Microenvironment Interactions with the microenvironment like angiogenesis and tumor-promoting inflammation.

De Novo Resistance De novo resistance limits the initial treatment response and may instigate alternative approaches. Some breast cancer cells have drug resistance because of their pre-existing genetic alterations.

Activation of innate mechanisms that guard against harmful foreign chemicals [27]; the presence of genetic mutations; and the exRelapse and metastases are common outcomes of chemotherapy due to multidrug resistance (MDR). Roughly half of all cases of activation of innate mechanisms that guard against harmful foreign chemicals [27]; the presence of genetic mutations; the expansion of insensitive subpopulations such as cancer stem cells; and the start of therapy. Acquired resistance, on the other hand, may arise through a number of different mechanisms, including the activation of proto-oncogenes, changes in gene expression as a consequence of mutations or epigenetic markers, and shifts in the tumor microenvironment. In BC, resistance may occur through a number of different pathways. Among them are alterations in drug efflux, senescence, DNA repair, tumor heterogeneity, tumor microenvironment (TME), epigenetic changes, and epithelial-to-mesenchymal transition (EMT) [27]. The tumor microenvironment, accelerated DNA repair, the epithelial-to-mesenchymal transition (EMT), epigenetic alterations, and increased drug efflux are all mechanisms of drug resistance in breast cancer.

Moreover, Epigenetic modifications have emerged as crucial regulators of drug resistance. For instance, aberrant methylation, histone modifications, and miRNA dysregulation have been identified as key mediators of altered gene expression patterns in resistant breast cancer cells [28]. This chapter highlights the complex interplay between cancer cells and stromal components, such as immune cells, cancer-related fibroblasts, and the therapeutic response matrix, influencing tumor growth, metastasis, and therapeutic response. Immune evasion mechanisms, including the upregulation of immune checkpoint proteins, have emerged as important contributors to immunotherapy resistance [29]. Table 11.4 shows the dysregulated microRNAs related to chemo-resistant breast cancer patients based on transcriptome analysis.

Table .4: The dysregulated microRNAs related to chemo-resistant breast cancer patients based on transcriptome scrutiny [25]

MicroRNA Expression Fold Change

Has-miR-195a-5p Upregulated 5.44

Has-miR-4266 Upregulated 3.45

Has-miR-200b-3p Upregulated 3.11

Has-miR-214-3p Upregulated 2.99

Has-miR-107 Upregulated 2.65

Has-miR-4454 Upregulated 2.77

Has-miR-5100 Upregulated 2.40

Has-miR-23a-3p Upregulated 2.31

Has-miR-23b-3p Upregulated 2.09

Has-miR-16-5p Upregulated 2.14

Has-miR-4707-5p Downregulated0.58

Has-miR-3656 Downregulated0.36

Has-miR-1233-1-5p DownregulatedUnregulated

Has-miR-3621 DownregulatedUnregulated

Has-miR-3141 DownregulatedUnregulated

Has-miR-489 DownregulatedUnregulated

Has-miR-1227-5p DownregulatedUnregulated

Has-miR-1275 DownregulatedUnregulated

Has-miR-1268b Downregulated0.41

Has-miR-572 Downregulated0.35

Has-miR-4467 Downregulated0.20

Has-miR-4472 Downregulated0.18

Although RNAs can be associated with chemoresistance, research has noted the necessity of identifying the targeted genes regulated by long noncoding RNAs and the interactions among these genes.

Undiscovered Genes and Signaling Pathways:

In addition to the significant advances in understanding drug resistance, this review revealed several gaps in knowledge, especially regarding the undiscovered genes and signaling pathways implicated in the resistance process. Promising preclinical studies have suggested that the involvement of novel genes and regulatory networks is yet to be fully explored [30]. The findings from these studies underscore the need for comprehensive functional genomics approaches to uncover the hidden molecular drivers of resistance in breast cancer. For instance, a study highlighted that the biological functions of genes in the eCB signaling pathway, based on protein-protein interactions, were associated with mitochondrial function in MDD from a genetic and biological function perspective [30]. Table 11.5 summarizes the seven hub genes mutated in the eCB pathway in MDD patients.

Table 5: The seven hub genes mutated in eCB pathways in patients with MDD [23]

Gene NDU FS4 NDUFV2 NDUFA2

MDD C0011 D0041 C0025 D0030

Chr5 5 18 5

Crytoband5q11.2 5q11.2 18p1122 Rs79526416

dbSNP Rs1064793807 Rs886060697 G T

Ref GTG TTTG C C

Alt CTC - Splicing Missense

ClinvarNonframeshift block substitution Splicing NA Uncertain significance

1KGP Likely benign Conflicting interpretations of pathogenicity NA 0.00079872

ExACNA 0.00139776 0.00001653 0.0001

gnomANA 0.0032 0.00001219 0.00232

Huabiao project NA 0.003 0.0001 0.000123

Biomarkers for Resistance to Systemic Therapy:

Identifying reliable biomarkers to predict and monitor drug resistance in breast cancer is a critical area of research [31]. This review shows that several potential biomarkers are associated with treatment response and resistance [32]. For instance, circulating tumor DNA (ctDNA) has emerged as a promising non-invasive biomarker that provides real-time information on tumor evolution and acquired mutations [32]. In addition, gene expression signatures and proteomic profiles were investigated to determine their predictive value in guiding treatment decisions. Table 11.6 summarizes the characteristics of the breast cancer cell lines in the suspension culture.

Table 6 Characteristics of the breast cancer cell lines in the suspension culture

Breast cancer molecular subtypes in suspension culture Cell line subgroups 5n suspension culture

Luminal A &B Luminal

Basal-like & claudin-low Basal A

Basal B

Hormonal Drug Resistance in Breast Cancer:

Hormone receptor-positive (HR+) breast cancer is a common subtype of breast cancer that is driven by the presence of estrogen and/or progesterone receptors on the surface of cancer cells. These receptors allow the cancer cells to respond to hormonal signals, which can promote their growth and survival. Hormone therapy is often used as a treatment for HR+ breast cancer. It works by blocking the effects of estrogen or suppressing its production, thereby inhibiting the growth of hormone-sensitive cancer cells. However, over time, some HR+ breast cancers can develop resistance to hormone therapy, leading to disease progression and reduced treatment effectiveness. There are several mechanisms that contribute to the development of hormonal drug resistance in breast cancer. These mechanisms are discussed below

Figure No. 3 Mechanism of Hormonal Drug Resistance in Breast Cancer

Acquired Mutations:

Cancer cells can acquire genetic mutations that alter the function of estrogen receptors or related signaling pathways. These mutations can make the cancer cells less dependent on estrogen for growth, rendering hormone therapy less effective. Evidence from research shows that the ER positive breast cancer makes up to 80% of the worlds breast cancers diagnosed among individuals. Further, research reveals that the ESR1 mutations alter the conformation of ER producing a constitutively active form of the protein. The study was justified by utilizing a stratified and regulated test for the recurrent mutations within the ligand-binding domain of ESR1 in 30% of ER positive MBC. The identified mutation alterations lower the SERMs sensitivity because of AIs resistance. There is sufficient research reporting the different types of breast cancers and circulating tumor DNA samples including other ESR1 fusion genes. Recurrent ESR1 fusion genes discovery strengthens the concept that resistance to targeted therapies often represent a convergent phenotype. As a result, the ESR1 is highly affected in case of resistance to endocrine therapy.

Crosstalk and Bypass Pathways:

Cancer cells can activate alternative signaling pathways that promote growth and survival, bypassing the need for estrogen signaling. For example, some cells may activate growth factor receptors like HER2 (human epidermal growth factor receptor 2) or other intracellular pathways that can promote cell growth independently of hormonal signaling.

Alterations in Estrogen Receptor:

Changes in the estrogen receptor itself can make it less responsive to hormonal therapy. This might involve mutations, receptor gene amplification, or other modifications that allow the receptor to remain active even in the absence of estrogen.

Micro-environmental Factors:

The tumor microenvironment can influence the response to therapy. Interactions between cancer cells and surrounding cells, such as immune cells and stromal cells, can promote resistance by providing survival signals or altering the way the tumor responds to therapy.

Epigenetic Changes:

Epigenetic modifications, which affect gene expression without altering the underlying DNA sequence, can lead to changes in hormone receptor expression and signaling pathways, contributing to resistance.

Heterogeneity:

Tumors are often composed of a mixture of different cancer cell populations. Some cells may inherently be less responsive to hormone therapy or have a higher propensity for developing resistance.

HOW TO OVERCOME HORMONAL DRUG RESISTANCE IN BREAST CANCER

Understanding the molecular pathways that contribute to drug resistance is essential. Evaluation of prognostic indicators as well as clinical and pathological characteristics informs the treatment choice for the management of patients with breast cancer. Although this method has been effective, some individuals relapse and/or acquire resistance over time. Overcoming hormonal drug resistance in breast cancer is difficult, although there are several approaches and therapeutic options that may help. These include;

Combining treatments: A combination of different hormonal therapeutic options with the focused mode of treatment can be more effective in the treatment of breast cancer. Using drugs with different working mechanisms can help in overcoming drug resistance. For instance, combining aromatase inhibitor with CDK4/6 inhibitor.

Changing hormonal treatments: Resistance may develop to a particular hormonal therapy as opposed to the other. Hence, using a different hormonal therapy will help in overcoming such resistance.

Targeted therapies: Breast cancer cells may even develop resistance through the activation of optional pathways. The application of targeted therapies that hinder these particular pathways can resolve drug resistance issues. A good example of this approach is the application of mTOR inhibitors combined with hormonal treatment to treat hormone receptor-positive breast cancer.

Genetic testing: Understanding particular genetic mutations through genetic testing in breast cancer can help in applying the correct therapeutic decision. In case of failure, tumor's genetic profile may be reevaluated to opt for a new treatment option that aligns with the genetic nature.

PAST AND CURRENT BC CLINICAL TRIALS:

BC is present around the milk ducts and lobules. However, it is considered in situ; thus, cancer has not yet manifested and diverged into the rest of the breast. Table 11.7 summarizes previous and current BC clinical trials concerning HER2, PARP, EGFR, AhR, iNOS, and Wnt.

Table 7: Past and current BC clinical trials concerning HER2, PARP, EGFR, AhR, iNOS, and WntIntervention/Therapy Target cancer subtype Clinical 1 trial phase Type Status Trial ID reference

KU 0059436 (olaparib), a PARP inhibitor BRCAL or BRCA2-positive advanced BC Phase 11 Treatment Active NCT00494234

Preoperative combination of letozole, everolimus, and TRC105everolimus and TRC105 Postmenopausal hormone-receptor positive ad Her2BC positive and Her2 BC Phase 1 Treatment Active NCT02520063

CDK4/6-inhibitor or chemotherapy, in combination with endocrine therapy Advanced BC Phase II Treatment Recruiting NCT03227328

LGK974 in patients with malignancies dependent on Wnt ligands TNBC Phase 1 Treatment Recruiting NCT01351103

IN VITRO AND IN VIVO MODELS FOR STUDYING DRUG RESISTANCE:

Preclinical studies have used various in vitro and in vivo models better to understand the complexities of drug resistance in breast cancer. Cell line-based models, patient-derived xenografts (PDX), and genetically modified mouse models (GEMMs) were frequently used to replicate tumor heterogeneity and medication responses [32]. Insights into the relationship between tumor and stroma and treatment sensitivity were gained using organoid cultures and 3D tumor models. The assessment also admits that none of the models adequately capture the complexity of medication resistance seen in clinical settings. Figure 11.4 summarizes the results and procedures.

Fig 4 Procedures and results

Emerging Strategies for Overcoming Drug Resistance:

Innovative strategies have been explored to sensitize breast cancer cells to therapies aimed at overcoming drug resistance. Combination therapies targeting multiple signaling pathways, exploiting synthetic lethality, and harnessing the immune system's potential are among the most promising approaches [33]. Targeting resistance-conferring mutations using gene-editing technologies and small-molecule inhibitors has shown encouraging preclinical results, which has motivated further investigation.

Biomarkers for Resistance Prediction:

This Chapter highlights the potential of various biomarkers for predicting and monitoring drug resistance in breast cancer, including ctDNA, gene expression signatures, and proteomic profiles. These biomarkers hold promise for guiding treatment decisions and facilitating early intervention. Nevertheless, the validation and standardization of these biomarkers in large clinical cohorts remain crucial for their successful translation into clinical practice.

In vitro and in vivo Models:The analysis of in vitro and in vivo models emphasizes the importance of using diverse and relevant systems to study drug resistance. Combining different models to complement each other's strengths and weaknesses may provide a more comprehensive understanding of the resistance mechanisms as shown in the below table 11.8. Although these models offer valuable insights, they inherently lack the complexity of the human tumor microenvironment, necessitating caution when translating preclinical findings to clinical settings.

Table 8: In vitro and In vivo models

Vitro Vivo

Isolated cellular components are used. Uses whole living organism

Consumes less time Consumes more time

Less precise More precise

Performed under controlled lab conditions Performed under physiological conditions

Cell structure experiment is in Petri dishes and test tubes Drug testing experiments performed through model organisms like mice.

Overcoming Drug Resistance:

Exploration of emerging strategies to overcome drug resistance has revealed the potential of combination therapies and immune-based approaches. Rational design of combination regimens targeting multiple pathways and vulnerabilities may effectively circumvent resistance. The promise of gene-editing technologies for targeting resistance-conferring mutations warrants further exploration, although safety and off-target effects remain important considerations.

Implications and Limitations:

The findings of this chapter have significant implications in breast cancer treatment and precision medicine. Understanding the diverse molecular drivers of drug resistance can aid in tailoring therapeutic approaches for individual patients, potentially leading to improved outcomes. Moreover, the identification of novel biomarkers and therapeutic targets opens new avenues for personalized treatment strategies. However, this study had several limitations. The reliance on published data limits the scope of our analysis to the available literature and the potential for publication bias cannot be disregarded. Additionally, the rapid pace of research in this field may result in outdated findings. Despite our efforts to include the most relevant studies, some valuable contributions may have been omitted.

Future Directions:

Several directions for future research have emerged, based on the identified knowledge gaps and limitations. It is essential to conduct large-scale prospective studies to validate biomarkers' predictive value in clinical practice [34]. Exploring the potential of novel gene editing techniques and synthetic lethality approaches in preclinical models may pave the way for innovative therapeutic interventions [34]. Additionally, investigating the impact of tumor heterogeneity and dynamic changes in the tumor microenvironment on drug resistance would be instrumental in devising more effective treatment strategies.

DISCUSSION:

A comprehensive review of the literature on drug resistance in breast cancer provides valuable insights into the complex molecular mechanisms underlying this phenomenon. This section discusses the key findings and implications of the results, highlights the studys limitations, and proposes future research directions. Previous research has aligned with the identified mechanisms of drug resistance in breast cancer, collaborating with the importance of genetic alterations, epigenetic modifications, and the tumor microenvironment in shaping therapeutic responses. Moreover, this study underscores the significance of specific mutations in targeted therapies [33]. Consequently, the emergence of novel genes and signaling pathways as potential contributors to resistance highlights the need for ongoing investigations to fully elucidate their roles.

CONCLUSIONS:

This review article comprehensively analyses the molecular mechanisms underlying drug resistance in breast cancer. These findings highlight the complexity and heterogeneity of resistance mechanisms involving genetic alterations, epigenetic changes, and the tumor microenvironment. The identification of key target mutations, undiscovered genes, and signaling pathways will provide a basis for future research in this area. This review also emphasizes the potential of biomarkers, such as ctDNA and gene expression signatures, for predicting and monitoring drug resistance. These biomarkers hold promise for guiding treatment decisions and improving patient outcomes. However, further validation and standardization in large clinical cohorts are necessary for its successful implementation in clinical practice. Moreover, our exploration of in vitro and in vivo models has revealed the importance of using diverse and relevant systems to study drug resistance. Combining different models to complement each other's strengths and weaknesses may enhance our understanding of the resistance mechanisms. Nevertheless, the limitations of preclinical models in fully recapitulating the complexity of drug resistance in patients warrant careful interpretation of the results and cautious clinical translation. Emerging strategies to overcome drug resistance, including combination therapies and immune-based approaches, offer hope for improved treatment outcomes. The potential of gene-editing technologies for targeting resistance-conferring mutations holds promise, although safety and specificity remain critical considerations. Considering the identified knowledge gaps and limitations, future research should focus on conducting large-scale prospective studies to validate biomarkers and explore the potential of novel therapeutic approaches. Investigating the impact of tumor heterogeneity and dynamic changes in the tumor microenvironment on drug resistance would be instrumental in devising more effective treatment strategies.

CONFLICTS OF INTEREST: The authors declare no potential conflicts of interest with respect to the research, authorship and/or publication of this chapter.

COPYRIGHT AND PERMISSION STATEMENT: The authors affirm that the materials included in this chapter do not violate copyright laws. Where relevant, appropriate permissions were obtained from the original copyright holder(s) and all original sources were appropriately acknowledged or referenced. Where relevant, informed consent was obtained from the patients or their caregivers according to the applicable national or institutional policies.

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