Acquired FGFR and FGF alterations confer resistance to estrogen receptor (ER) targeted therapy in ER+ metastatic breast cancer
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ABSTRACT:
PROVIDER: PRJNA642877 | ENA |
REPOSITORIES: ENA
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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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Project description:Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to ER-directed therapies
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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.
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Project description:The human fibroblast growth factor/fibroblast growth factor-receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenström’s Macroglobulinemia (WM). WM is still an incurable disease, and patients succumb due to disease progression. Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We aimed to investigate the role of FGF/FGFR blocking system in WM by using a pan-FGF trap molecule (NSC12). Wide-transcriptome profiling confirmed inhibition of FGFR-signaling in NSC12-treated WM cells; unveiling a significant inhibition of Myd88 also confirmed at protein level. Importantly, the NSC12-dependent silencing of Myd88 was functionally active, as it led to inhibition of Myd88-driven pathways, such as BTK and SYK, as well as the Myd88-downstream target HCK. Of note, both canonical and non-canonical NFB cascades were down-regulated in WM cells upon NSC12 treatment. Functional sequelae exerted by NSC12 in WM cells were studied, demonstrating significant inhibition of WM cell growth, induction of WM cell apoptosis, halting MAPK, JAK/STAT3 and PI3K-Akt pathways. Importantly, NSC12 exerted an anti-WM effect even in the presence of bone marrow microenvironment, both in vitro and in vivo. Our studies provide the evidence for using NSC12 as a specific FGF/FGFR system inhibitor, thus representing a novel therapeutic strategy in WM.
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Project description:The challenge of developing effective pharmacodynamic biomarkers for pre-clinical and clinical testing of FGFR signalling inhibition is significant. Assays that rely on the measurement of phospho-protein epitopes can be limited by the availability of effective antibody detection reagents. Transcript profiling enables accurate quantification of many biomarkers and a broader representation of pathway modulation. To identify dynamic transcript biomarkers of FGFR signalling inhibition by AZD4547, a potent inhibitor of FGF receptor 1, 2 and 3, a gene expression profiling study was performed in FGFR2 amplified drug sensitive tumour cell lines.
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Project description:Acquired resistance of gastrointestinal stromal tumors (GISTs) to imatinib mesylate (IM) is one of the most critical challenges in GIST therapy. Here we show that a long-term culture of GIST T-1 cells with IM induces clonal heterogeneity resulting in the appearance of cancer cells exhibiting activation of the FGFR-signaling pathway which was associated with KIT loss. The first one was due to the overexpression of FGFR1/2 and increased production of FGF-2 ligand. These events maintained GIST resistance to IM and rendered these GIST cells highly sensitive to all types of pan-FGFR-inhibitors used in the current study. Knockout of FGFR2 in this GIST subclone significantly attenuated pro-apoptotic and anti-proliferative activities of infigratinib (BGJ 398) both in vitro and in vivo, thereby suggesting the activation of FGFR-signaling pathway via FGFR2-mediated axis as the predominant molecular mechanism in these GIST cells. Collectively, the extended inhibition of KIT-signaling in GISTs induces clonal heterogeneity of cancer cells and might change the tumor’s sensitivity to FGFR-inhibitors due to selection of cancer cells with an FGFR-overactivated pathway.
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Project description:Cooperation between FGF and WNT signaling is well documented in normal development, stem cell biology and cancer progression. However, the molecular mechanisms underlying this cooperativity remain poorly understood. In this study, we employed an inducible FGFR1 to interrogate the dynamics of RNA, ribosome occupancy and protein expression as a function of FGFR signaling in the mouse mammary gland with constitutive WNT hyperactivation. We demonstrate that FGFR signaling increases the translation efficiency of WNT signaling components with structured 5’ UTRs harboring a (CGG)4 motif that can potentially form G-quadruplex structures, and that tumorigenesis driven by this mechanism is vulnerable to inhibition of eIF4A, a RNA helicase important in translation initiation. This study also provides novel insights into the contribution of RNA levels and translational regulation to protein expression in pre-malignant mammary epithelial cells dynamically responding to FGFR signaling.
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Project description:FGFR signalling is one of the most prominent pathways involved in cell growth and development, as well as cancer progression. FGFR1 amplification occurs in approximately 20% of all squamous cell lung carcinomas (SCC) - one of the most common subtypes of non-small cell lung carcinoma (NSCLC), indicating FGFR as a potential target for the new anti-cancer therapies. However, acquired resistance to this type of therapies remains a clinical issue. Here, we investigated the NSCLC cell lines response and potential mechanism of acquired resistance to novel selective FGFR inhibitor CPL304110. We found that despite significant genomic differences between CPL304110-sensitive cell lines, their resistant variants were characterized by upregulated p38 expression/phosphorylation, as well as enhanced expression of genes involved in MAPK signalling. We revealed that p38 inhibition restored sensitivity to CPL304110 in these cells. Moreover, overexpression of this kinase in parental cells led to impaired response to FGFR inhibition, thus confirming that p38 MAPK is a driver of resistance to a novel FGFR inhibitor. Taken together, our results provide an insight into the potential direction for NSCLC targeted therapy.
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Project description:FGFR signalling is one of the most prominent pathways involved in cell growth and development, as well as cancer progression. FGFR1 amplification occurs in approximately 20% of all squamous cell lung carcinomas (SCC) - one of the most common subtypes of non-small cell lung carcinoma (NSCLC), indicating FGFR as a potential target for the new anti-cancer therapies. However, acquired resistance to this type of therapies remains a clinical issue. Here, we investigated the NSCLC cell lines response and potential mechanism of acquired resistance to novel selective FGFR inhibitor CPL304110. We found that despite significant genomic differences between CPL304110-sensitive cell lines, their resistant variants were characterized by upregulated p38 expression/phosphorylation, as well as enhanced expression of genes involved in MAPK signalling. We revealed that p38 inhibition restored sensitivity to CPL304110 in these cells. Moreover, overexpression of this kinase in parental cells led to impaired response to FGFR inhibition, thus confirming that p38 MAPK is a driver of resistance to a novel FGFR inhibitor. Taken together, our results provide an insight into the potential direction for NSCLC targeted therapy.
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