scholarly journals The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer

2019 ◽  
Author(s):  
Seth A. Wander ◽  
Ofir Cohen ◽  
Xueqian Gong ◽  
Gabriela N. Johnson ◽  
Jorge Buendia-Buendia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
Resistance Mechanisms ◽  
Akt Activation ◽  
Hormone Receptor Positive ◽  
Ras Activation ◽  
Whole Exome ◽  
Clinical Resistance

AbstractClinical resistance mechanisms to CDK4/6 inhibitors in HR+ breast cancer have not been clearly defined. Whole exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of ER expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Besides inactivation of RB1, which accounts for ∼5% of resistance, seven of these mechanisms have not been previously identified as clinical mediators of resistance to CDK4/6 inhibitors in patients. Three of these—RAS activation, AKT activation, and AURKA activation—have not to our knowledge been previously demonstrated preclinically. Together, these eight mechanisms were present in 80% of resistant tumors profiled and may define therapeutic opportunities in patients.SignificanceWe identified eight distinct mechanisms of resistance to CDK4/6 inhibitors present in 80% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ MBC.

scholarly journals Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

2020 ◽  
Vol 21 (18) ◽  
pp. 6479 ◽  
Author(s):  
Michela Piezzo ◽  
Stefania Cocco ◽  
Roberta Caputo ◽  
Daniela Cianniello ◽  
Germira Di Gioia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Clinical Outcomes ◽  
Cell Cycle Control ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
New Combination ◽  
Hormone Receptor Positive ◽  
Combination Strategies ◽  
New Biomarkers

Deregulation of cell cycle, via cyclin D/CDK/pRb pathway, is frequently observed in breast cancer lending support to the development of drugs targeting the cell cycle control machinery, like the inhibitors of the cycline-dependent kinases (CDK) 4 and 6. Up to now, three CDK4/6 inhibitors have been approved by FDA for the treatment of hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. These agents have been effective in improving the clinical outcomes, but the development of intrinsic or acquired resistance can limit the efficacy of these treatments. Clinical and translational research is now focused on investigation of the mechanism of sensitivity/resistance to CDK4/6 inhibition and novel therapeutic strategies aimed to improve clinical outcomes. This review summarizes the available knowledge regarding CDK4/6 inhibitor, the discovery of new biomarkers of response, and the biological rationale for new combination strategies of treatment.

scholarly journals YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1) Resistance Development

2021 ◽  
Vol 22 (23) ◽  
pp. 12809
Author(s):  
Miwa Fujihara ◽  
Tadahiko Shien ◽  
Kazuhiko Shien ◽  
Ken Suzawa ◽  
Tatsuaki Takeda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Resistance Mechanisms ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Trastuzumab Emtansine ◽  
Her2 Positive

Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying T-DM1 resistance after the development of acquired resistance to trastuzumab. We previously reported that YES1, a member of the Src family, plays an important role in acquired resistance to trastuzumab in HER2-amplified breast cancer cells. We newly established a trastuzumab/T-DM1-dual-resistant cell line and analyzed the resistance mechanisms in this cell line. At first, the T-DM1 effectively inhibited the YES1-amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. YES1 amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the YES1 or the administration of the Src inhibitor dasatinib restored sensitivity to T-DM1. Our results indicate that YES1 is also strongly associated with T-DM1 resistance after the development of acquired resistance to trastuzumab, and the continuous inhibition of YES1 is important for overcoming resistance to T-DM1.

Treatment Algorithms for Hormone Receptor-Positive Advanced Breast Cancer: Applying the Results from Recent Clinical Trials into Daily Practice—Insights, Limitations, and Moving Forward

2013 ◽  
pp. e20-e27
Author(s):  
Sheridan Wilson ◽  
Stephen K. Chia
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Acquired Resistance ◽  
Mammalian Target Of Rapamycin ◽  
Real Life ◽  
Metastatic Breast ◽  
Predictive Biomarkers ◽  
Endocrine Treatment ◽  
First Line ◽  
Hormone Receptor Positive

Hormone receptor–positive (HR+) breast cancer is the most prevalent subtype of breast cancer in both early- and advanced-stage disease. Thus, the treatment of HR+ breast cancer has had the greatest global influence in improving clinical outcomes overall. Although the first-line metastatic breast cancer (MBC) trials comparing a third-generation aromatase inhibitor (AI) to tamoxifen have favored the AI, one of the challenges in translating these findings into clinical practice stems from the influence of prior adjuvant endocrine therapy, particularly the increasing use of adjuvant AIs today, on the choice of endocrine agent in the advanced setting because of the development of acquired resistance. Because the majority of patients enrolled into these studies were either endocrine-treatment naïve or exposed to tamoxifen only, the “real-life” applicability of the evidence is unclear. Because a superior dose of the selective estrogen receptor (ER) downregulator fulvestrant has now been established, its role as first-line therapy is being re-established. We are now starting to see the promise realized with blocking cross-talking growth factor pathways in addition to the ER pathway. The greatest efficacy is seen with the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with exemestane and, perhaps to a lesser extent, anti-HER2–directed therapy in combination with an AI. Future gains will likely involve a greater understanding of the redundancy and compensation induced by blocking these pathways, trials involving blocking multiple pathways in addition to hormonal agents, and the molecular interrogation of the individual's tumor in search of predictive biomarkers and “actionable” genomic aberrations.

scholarly journals Assessment of Resistance Mechanisms and Clinical Implications in Patients with KRAS Mutated-Metastatic Breast Cancer and Resistance to CDK4/6 Inhibitors

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1928
Author(s):  
Lucrezia Raimondi ◽  
Filippo Maria Raimondi ◽  
Marta Pietranera ◽  
Arianna Di Rocco ◽  
Laura Di Benedetto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Resistance Mechanisms ◽  
Kras Mutations ◽  
Hormone Receptor Positive ◽  
Treatment Plans ◽  
Epidermal Growth

Despite therapeutic improvements, resistance to palbociclib is a growing clinical challenge which is poorly understood. This study was conducted in order to understand the molecular mechanisms of resistance to palbociclib, and to identify biomarkers to predict who will take advantage from cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). A total of about a thousand blood samples were collected from 106 patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer who received palbociclib in combination with fulvestrant as the first-line metastatic therapy enrolled in this study. The genotyping of their plasma cell-free DNA was studied, including serial plasma samples. Collectively, our findings identify the appearance of KRAS mutations leading to palbociclib resistance acquisition within 6 months, and provide critical information for the prediction of therapeutic responses in metastatic breast cancer. By monitoring KRAS status through liquid biopsy, we could predict who will take advantage from the combination of palbociclib and fulvestrant, offering highly-individualized treatment plans, thus ensuring the best patient quality of life.

scholarly journals Circulating Biomarkers of CDK4/6 Inhibitors Response in Hormone Receptor Positive and HER2 Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2640
Author(s):  
Ilenia Migliaccio ◽  
Angela Leo ◽  
Francesca Galardi ◽  
Cristina Guarducci ◽  
Giulio Maria Fusco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
Circulating Tumor Dna ◽  
Breast Cancer Patients ◽  
Circulating Biomarkers ◽  
Hormone Receptor Positive ◽  
Her2 Breast Cancer ◽  
Monitoring Treatment

CDK4/6 inhibitors (CDK4/6i) and endocrine therapy are the standard treatment for patients with hormone receptor-positive and HER2 negative (HR+/HER2−) metastatic breast cancer. Patients might show intrinsic and acquired resistance, which leads to treatment failure and progression. Circulating biomarkers have the potential advantages of recognizing patients who might not respond to treatment, monitoring treatment effects and identifying markers of acquired resistance during tumor progression with a simple withdrawal of peripheral blood. Genomic alterations on circulating tumor DNA and serum thymidine kinase activity, but also circulating tumor cells, epigenetic or exosome markers are currently being tested as markers of CDK4/6i treatment response, even though none of these have been integrated into clinical practice. In this review, we discuss the recent advancements in the development of circulating biomarkers of CDK4/6i response in patients with HR+/HER2−breast cancer.

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