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Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer
Neil Portman1,2, Sarah Alexandrou1,2, Emma Carson1,2
1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Abstract:
Three inhibitors of CDK4/6 kinases were recently FDA approved for use in combination with endocrine therapy, and they significantly increase the progression-free survival of patients with advanced estrogen receptor-positive (ER+) breast cancer in the first-line treatment setting. As the new standard of care in some countries, there is the clinical emergence of patients with breast cancer that is both CDK4/6 inhibitor and endocrine therapy resistant. The strategies to combat these cancers with resistance to multiple treatments are not yet defined and represent the next major clinical challenge in ER+ breast cancer. In this review, we discuss how the molecular landscape of endocrine therapy resistance may affect the response to CDK4/6 inhibitors, and how this intersects with biomarkers of intrinsic insensitivity. We identify the handful of pre-clinical models of acquired resistance to CDK4/6 inhibitors and discuss whether the molecular changes in these models are likely to be relevant or modified in the context of endocrine therapy resistance. Finally, we consider the crucial question of how some of these changes are potentially amenable to therapy.
Insights
New treatments combining CDK4/6 inhibitors and endocrine therapy improve survival for advanced ER+ breast cancer. However, resistance is emerging, posing a significant clinical challenge requiring new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- CDK4/6 inhibitors combined with endocrine therapy are FDA-approved for advanced ER+ breast cancer, improving progression-free survival.
- Emerging clinical resistance to both CDK4/6 inhibitors and endocrine therapy presents a new challenge in ER+ breast cancer treatment.
Purpose of the Study:
- To review the molecular mechanisms of endocrine therapy resistance and their impact on CDK4/6 inhibitor response.
- To explore the intersection of endocrine therapy resistance biomarkers and intrinsic insensitivity to CDK4/6 inhibitors.
- To evaluate pre-clinical models of acquired CDK4/6 inhibitor resistance in the context of endocrine therapy resistance.
Main Methods:
- Literature review of pre-clinical models and molecular mechanisms.
- Analysis of biomarker data related to treatment resistance.
- Discussion of potential therapeutic strategies for resistant cancers.
Main Results:
- The molecular landscape of endocrine therapy resistance influences response to CDK4/6 inhibitors.
- Pre-clinical models of acquired resistance to CDK4/6 inhibitors are limited but offer insights.
- Some molecular alterations conferring resistance may be therapeutically targetable.
Conclusions:
- Understanding the interplay between endocrine therapy and CDK4/6 inhibitor resistance is crucial.
- Further research into pre-clinical models is needed to elucidate resistance mechanisms.
- Identifying and targeting resistance pathways is the next frontier in treating advanced ER+ breast cancer.
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