Targeted therapy for breast cancer and molecular mechanisms of resistance to treatment

Gu, Guowei; Dustin, Derek; Fuqua, Suzanne A.W.

doi:10.1016/j.coph.2016.11.005

Cited by 135 publications

(104 citation statements)

References 54 publications

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“…The details of these mechanisms are beyond the scope of this review but have been thoroughly described by others [23,24]. The complexity of ER function in tumor cells underscores the heterogeneity of breast cancer biology and demonstrates a necessity for continued basic research and clinical demonstration to effectively target the pathways essential to tumor cell survival.…”

Section: Introductionmentioning

confidence: 95%

Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors

Mills

Rutkovsky

Giordano

2018

Current Opinion in Pharmacology

123

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Several mechanisms of resistance have been identified, underscoring the complex nature of estrogen receptor (ER) signaling and the many connections between this pathway and other essential signaling pathways in breast cancer cells. Many therapeutic targets of cell signaling and cell cycle pathways have met success with endocrine therapy and remain an ongoing area of investigation. This review focuses on two major pathways that have recently emerged as important opportunities for therapeutic intervention in endocrine resistant breast tumors: PI3K/AKT/mTOR cell signaling and cyclinD1/cyclin-dependent kinase 4/6 cell cycle pathways. Additionally, we highlight individual and combination strategies in current clinical trials that target these pathways and others under investigation for the treatment of ER positive breast cancer.

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Section: Introductionmentioning

confidence: 95%

Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors

Mills

Rutkovsky

Giordano

2018

Current Opinion in Pharmacology

123

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“…tamoxifen, and inhibitors of the enzyme aromatase, involved in oestrogen synthesis) for ER-positive disease, and trastuzumab (Herceptin) for HER2-positive breast cancer; however, drug resistance to these regimes is common (Osborne and Schiff, 2011; Palmieri et al, 2014; Luque-Cabal et al, 2016). Furthermore, there is still no good targeted therapy for triple-negative breast cancer, which is one of the more aggressive subtypes of the disease (Kalimutho et al, 2015; Gu et al, 2016). In addition, whilst primary breast cancer is highly treatable [80-99% of women diagnosed with stage I/II breast cancer survive to 5 years; (; )], there is no cure currently available for metastatic breast cancer, which affects an estimated 40% of UK patients () and likely accounts for the decline in survival rate to 65% at 20 years post-diagnosis.…”

Section: Introductionmentioning

confidence: 99%

In vivomodels in breast cancer research: progress, challenges and future directions

Holen

Speirs

Morrissey

et al. 2017

Disease Models &Amp; Mechanisms

146

121

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Research using animal model systems has been instrumental in delivering improved therapies for breast cancer, as well as in generating new insights into the mechanisms that underpin development of the disease. A large number of different models are now available, reflecting different types and stages of the disease; choosing which one to use depends on the specific research question(s) to be investigated. Based on presentations and discussions from leading experts who attended a recent workshop focused on in vivo models of breast cancer, this article provides a perspective on the many varied uses of these models in breast cancer research, their strengths, associated challenges and future directions. Among the questions discussed were: how well do models represent the different stages of human disease; how can we model the involvement of the human immune system and microenvironment in breast cancer; what are the appropriate models of metastatic disease; can we use models to carry out preclinical drug trials and identify pathways responsible for drug resistance; and what are the limitations of patient-derived xenograft models? We briefly outline the areas where the existing breast cancer models require improvement in light of the increased understanding of the disease process, reflecting the drive towards more personalised therapies and identification of mechanisms of drug resistance.

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“…Among the antineoplastics commonly encountered in the aforementioned settings are those belonging to the taxane, platinum, and vinca alkaloid families. 2–6 Although efficacious, these agents are associated with significant, debilitating, adverse side effects, including chemotherapy-induced peripheral neuropathy (CIPN). As cancer survival rates have improved, 1,7 the burden of CIPN has correspondingly increased.…”

Section: Introductionmentioning

confidence: 99%

Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy

Aromolaran

Goldstein

2017

Mol Pain

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Cancer is the second leading cause of death worldwide and is a major global health burden. Significant improvements in survival have been achieved, due in part to advances in adjuvant antineoplastic chemotherapy. The most commonly used antineoplastics belong to the taxane, platinum, and vinca alkaloid families. While beneficial, these agents are frequently accompanied by severe side effects, including chemotherapy-induced peripheral neuropathy (CPIN). While CPIN affects both motor and sensory systems, the majority of symptoms are sensory, with pain, tingling, and numbness being the predominant complaints. CPIN not only decreases the quality of life of cancer survivors but also can lead to discontinuation of treatment, thereby adversely affecting survival. Consequently, minimizing the incidence or severity of CPIN is highly desirable, but strategies to prevent and/or treat CIPN have proven elusive. One difficulty in achieving this goal arises from the fact that the molecular and cellular mechanisms that produce CPIN are not fully known; however, one common mechanism appears to be changes in ion channel expression in primary afferent sensory neurons. The processes that underlie chemotherapy-induced changes in ion channel expression and function are poorly understood. Not all antineoplastic agents directly affect ion channel function, suggesting additional pathways may contribute to the development of CPIN Indeed, there are indications that these drugs may mediate their effects through cellular signaling pathways including second messengers and inflammatory cytokines. Here, we focus on ion channelopathies as causal mechanisms for CPIN and review the data from both pre-clinical animal models and from human studies with the aim of facilitating the development of appropriate strategies to prevent and/or treat CPIN.

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Targeted therapy for breast cancer and molecular mechanisms of resistance to treatment

Cited by 135 publications

References 54 publications

Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors

Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors

In vivomodels in breast cancer research: progress, challenges and future directions

Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy

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