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Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to ER-directed therapies

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE121411 | GEO | 2018/10/19

REPOSITORIES: GEO

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Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to ER-directed therapies

Project description:Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to ER-directed therapies

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Acquired FGFR and FGF alterations confer resistance to estrogen receptor (ER) targeted therapy in ER+ metastatic breast cancer

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.

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Phosphoproteomics of BYL719 (alpelisib)-Resistant T47D Human Breast Cancer Cell Line

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Gene expression analysis of ER+ and ER- breast cancer cell lines with acquired resistance to palbociclib

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.

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Transcription profiling of human in vivo xenograft models of estrogen receptor-positive (ER+) breast cancer, with or without HER2 over-expression (MCF7/HER2-18 and MCF7 wt, respectively)

Project description:To investigate molecular mechanisms of resistance, we used two different in vivo xenograft models of estrogen receptor-positive (ER+) breast cancer, with or without HER2 over-expression (MCF7/HER2-18 and MCF7 wt, respectively). Mice with established tumors were assigned to the following treatment groups: continued estrogen supplementation (E2), estrogen deprivation (ED), ED plus tamoxifen (Tam), all with or without the EGFR tyrosine kinase inhibitor gefinitinib (G). Another group received ED plus the antiestrogen fulvestrant (MCF7 wt only). Tumors with acquired or de novo resistance to these endocrine therapies were profiled for mRNA expression using Affymetrix Genechip arrays. Experiment Overall Design: MCF7 xenografts were established in ovariectomized five to six week-old nu/nu athymic nude mice supplemented with 0.25 mg 21 day release estrogen pellets by inoculating subcutaneously (s.c.) 5E-6 cells. When tumors reached the size of 150-200 mm3 (3-5 weeks), the animals were randomly allocated to continued estrogen (E2), continued estrogen with gefitinib (E2+G; 100mg/kg, 5 days/week), estrogen withdrawal alone (ED; by removal of the estrogen pellets), and estrogen withdrawal plus tamoxifen citrate (Tam; 500 microg/animal s.c. in peanut oil, 5 days/week), with either gefitinib (Tam+G; 100mg/kg, 5 days/week) or vehicle (1% Tween 80) administered via gavage, as well as estrogen withdrawal plus fulvestrant (ICI 182,780) in the MCF7 wt model (Fulv; 5mg/mouse s.c. once weekly), and estrogen withdrawal with gefitinib (ED+G). Tumors were harvested for molecular studies when they became resistant to treatment and reached the size of 1000 mm3 (n=7).

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Project description:The goal of the study was to understand whether mutations in ERa can promote resistance to various ERa antagonists of the SERD and SERM class. We found that ESR1 mutations can maintain higher ER pathway activity relative to control lines following short-term treatment with ERa antagonists raloxifene or fulvestrant.

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