Evolution of resistance in ER+ Breast Cancer
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PROVIDER: PRJNA678035 | ENA |
REPOSITORIES: ENA
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Project description:Evolution of resistance in ER+ Breast Cancer
| PRJNA678034 | ENA
Project description:Estrogen receptor positive (ER+) breast cancers that develop resistance to therapies that target the ER are the most common cause of breast cancer death. Beyond mutations in ER, which occur in 25-30% of patients treated with aromatase inhibitors (AIs), our understanding of clinical mechanisms of resistance to ER-directed therapies remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER+ metastatic breast cancer who had developed resistance to ER-directed agents, including AIs, tamoxifen, and fulvestrant. Examination of treatment-naïve primary tumors in five patients revealed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. These mutations were mutually exclusive with ER mutations, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that these mutations conferred estrogen independence. In addition, and in contrast to ER mutations, these mutations resulted in resistance to tamoxifen, fulvestrant, and the CDK4/6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib, highlighting an effective treatment strategy in these patients.
2018-10-19 | GSE121411 | GEO
Project description:Response and Resistance to ER-directed Therapy in ER+ Metastatic Breast Cancer
| PRJNA369715 | ENA
Project description:Beyond acquired mutations in the estrogen receptor (ER), mechanisms of resistance to ER-directed therapies in ER+ breast cancer have not been clearly defined. We conducted a genome-scale functional screen spanning 10,135 genes to investigate genes whose overexpression confer resistance to selective estrogen receptor degraders. Pathway analysis of candidate resistance genes demonstrated that the FGFR, ERBB, insulin receptor, and MAPK pathways represented key modalities of resistance. In parallel, we performed whole exome sequencing in paired pre-treatment and post-resistance biopsies from 60 patients with ER+ metastatic breast cancer who had developed resistance to ER-targeted therapy. The FGFR pathway was altered via FGFR1, FGFR2, or FGF3/FGF4 amplifications or FGFR2 mutations in 24 (40%) of the post-resistance biopsies. In 12 of the 24 post-resistance tumors exhibiting FGFR/FGF alterations, these alterations were not detected in the corresponding pre-treatment tumors, suggesting that they were acquired or enriched under the selective pressure of ER-directed therapy. In vitro experiments in ER+ breast cancer cells confirmed that FGFR/FGF alterations led to fulvestrant resistance as well as cross-resistance to the CDK4/6 inhibitor palbociclib, through activation of the MAPK pathway. The resistance phenotypes were reversed by FGFR inhibitors and, to a lesser extent, MEK inhibitors, suggesting potential treatment strategies.
2020-06-30 | GSE153509 | GEO
Project description:While targeted therapies directed against cancer cells have proven effective, their clinical benefit is often limited by acquired resistance. This clinical challenge underscores the importance of uncovering the molecular mechanisms behind resistance in order to develop novel targets and drug combinations that can stop the growth of cancer cells. Two pivotal pathways controlling tumor growth are glucose metabolism and cell cycle. PFKFB3 and CDK4/6 are key regulators of glucose metabolism and cell cycle respectively for which inhibitors have been developed. PFK158 is an inhibitor against PFKFB3 that is currently undergoing phase I clinical trials and has shown to be effective at blocking glucose metabolism in solid tumors. Palbociclib, a novel CDK4/6 inhibitor was recently approved as a first-line approach for the treatment of estrogen receptor (ER) positive breast cancer because of the very promising clinical responses in ER+ breast cancer patients. Unfortunately, the effects of these therapies are short-lasting since cancer cells ultimately develop resistance allowing them to escape treatment. To identify the molecular mechanisms driving resistance to PFK158 or palbociclib, we have generated ER+ MCF7 and ER- MDA-MB231 cells resistant to either PFK158 or palbociclib by continuous exposure to increasing doses of drugs for a period of three months. Our hypothesis is that resistance is driven by activating mutations and/or pathways acquired during the course of treatment. This study is designed to identify specific mutations and/or changes in gene expression responsible for the resistance to PFK158 or palbociclib in ER+ and ER- in vitro. The results of this study will lead to the development of new therapeutic strategies to overcome resistance to PFKFB3 and CDK4/6 inhibitors.
2019-06-20 | GSE130437 | GEO
Project description:RNA Expression Profiling Comparing ER+ Postpartum Breast Cancer with ER+ Nulliparous Breast Cancer
| PRJNA666701 | ENA
Project description:Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to ER-directed therapies
| PRJNA497449 | ENA
Project description:Combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy significantly improves the outcome of patients with advanced estrogen receptor-positive (ER+) breast cancer. However, resistance to this treatment and resultant disease progression remains a major clinical challenge. High expression of the receptor tyrosine kinase REarranged during Transfection (RET) has been associated with resistance to endocrine therapy in breast cancer, but the role of RET in CDK4/6i treatment response/resistance remains unexplored. To identify gene expression alterations associated with resistance to combined endocrine therapy and CDK4/6i, we performed global gene expression analysis and RNA sequencing of two ER+ breast cancer cell models resistant to this combined therapy.
2024-11-19 | GSE268699 | GEO
Project description:LiMe genes and ER-Breast cancer
| PRJNA523342 | ENA
Project description:The efficacy of hormonal therapies for advanced estrogen receptor-positive breast cancers is limited by the nearly inevitable development of acquired resistance. Efforts to block the emergence of resistance have met with limited success, largely because the mechanisms underlying it are so varied and complex. Here, we investigate a new strategy, aimed at the very processes by which cancers evolve resistance. From yeast to vertebrates, HSP90 plays a unique role amongst molecular chaperones by promoting the evolution of heritable new traits. It does so by regulating the folding of a diverse portfolio of metastable client proteins, many of which mediate adaptive responses that allow organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs. Guided by our previous work in pathogenic fungi where very modest HSP90 inhibition impairs resistance to mechanistically diverse antifungals, we examined the effect of similarly modest HSP90 inhibition on the emergence of resistance to anti-estrogens in breast cancer models. Even though this degree of inhibition fell below the threshold for proteotoxic activation of the heat-shock response and had no overt anticancer activity on its own, it dramatically impaired the emergence of resistance to hormone antagonists both in cell culture and in mice. Our findings strongly support the clinical testing of combined hormone antagonist-low level HSP90 inhibitor regimens in the treatment of metastatic ER+ breast cancer. At a broader level, they also provide promising proof-of-principle for a generalizable strategy to combat the pervasive problem of rapidly emerging resistance to molecularly targeted therapeutics.
2014-12-01 | GSE61906 | GEO