<i>FGFR1</i> Amplification Mediates Endocrine Resistance but Retains TORC Sensitivity in Metastatic Hormone Receptor–Positive (HR+) Breast Cancer

Drago, Joshua Z.; Formisano, Luigi; Juric, Dejan; Niemierko, Andrzej; Servetto, Alberto; Wander, Seth A.; Spring, Laura; Vidula, Neelima; Younger, Jerry; Peppercorn, Jeffrey; Yuen, Megan; Malvarosa, Giuliana; Sgroi, Dennis; Isakoff, Steven J.; Moy, Beverly; Ellisen, Leif W.; Iafrate, A. John; Arteaga, Carlos L.; Bardia, Aditya

doi:10.1158/1078-0432.ccr-19-0138

Cited by 61 publications

(46 citation statements)

References 29 publications

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“…Most notably, all four alterations in FGFR2 in our cohort were found to be acquired after the development of resistance to endocrine therapy. Our overall findings are consistent with other recent studies which noted some patients with acquired FGFR1 and FGFR2 alterations following treatment of endocrine therapy [37, 38, 44, 45], and provides a mechanistic explanation for these acquisitions.…”

Section: Discussionsupporting

confidence: 93%

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

Mao

Cohen

Kowalski

et al. 2019

Preprint

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55Beyond acquired mutations in the estrogen receptor (ER), mechanisms of resistance to 56 ER-directed therapies in ER+ breast cancer have not been clearly defined. We conducted 57 a genome-scale functional screen spanning 10,135 genes to investigate genes whose 58 overexpression confer resistance to selective estrogen receptor degraders. Pathway 59 analysis of candidate resistance genes demonstrated that the FGFR, ERBB, insulin 60 receptor, and MAPK pathways represented key modalities of resistance. In parallel, we 61 performed whole exome sequencing in paired pre-treatment and post-resistance biopsies 62 from 60 patients with ER+ metastatic breast cancer who had developed resistance to ER-63 targeted therapy. The FGFR pathway was altered via FGFR1, FGFR2, or FGF3 64 amplifications or FGFR2 mutations in 24 (40%) of the post-resistance biopsies. In 12 of 65 the 24 post-resistance tumors exhibiting FGFR/FGF alterations, these alterations were not 66 detected in the corresponding pre-treatment tumors, suggesting that they were acquired or 67 enriched under the selective pressure of ER-directed therapy. In vitro experiments in ER+ 68 breast cancer cells confirmed that FGFR/FGF alterations led to fulvestrant resistance as 69 well as cross-resistance to the CDK4/6 inhibitor palbociclib. RNA sequencing of resistant 70 cell lines treated with different drug combinations demonstrated that FGFR/FGF induced 71 resistance through ER reprogramming and activation of the MAPK pathway. The 72 resistance phenotypes were reversed by FGFR inhibitors, a MEK inhibitor, and/or a 73 SHP2 inhibitor, suggesting potential treatment strategies. The detection of targetable, 74 clonally acquired genetic alterations in the FGFR pathway in metastatic tumor biopsies 75 highlights the value of serial tumor testing to dissect mechanisms of resistance in human 76 breast cancer and its potential application in directing clinical management. 77 78 [4][5][6][7], acquired activating mutations in ERBB2 (HER2) [11, 12], loss of function of NF1 96[13], and other alterations in MAPK pathway genes [14]. Additional mechanisms remain 97 to be identified. 98 99 Gain-of-function screens have played a pivotal role in identification of resistance 100 mechanisms to targeted therapies in various cancer types [15-17]. In breast cancer, 101 5 several functional screen studies identified IGF1R, KRAS and ESR1 as mechanisms of 102 resistance to tamoxifen and/or estrogen deprivation [18-20]. However, genome-scale 103 functional screens for SERD resistance have not been reported. 104 105 We conducted a genome-scale gain-of-function screen in ER+ breast cancer cells 106 spanning 17,255 overexpressed lentiviral open reading frames (ORFs) to investigate 107 genes whose overexpression was sufficient to confer resistance to the SERDs fulvestrant 108 and GDC-0810 [21]. In parallel, we sought to identify endocrine resistance mechanisms 109 of clinical significance through genomic profiling of paired pre-treatment and post-110 treatment tumor samples from 60 patients with ER+ me...

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Section: Discussionsupporting

confidence: 93%

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

Mao

Cohen

Kowalski

et al. 2019

Preprint

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“…We confirm enrichment of activating mutations in ERBB2 and amplification events in FGFR2 in resistant patients, and both pathways provoke resistance to anti-estrogens and CDK4/6i in vitro. 24–26, 36 We present, to our knowledge, the first evidence implicating AKT1, RAS, and AURKA in mediating resistance to CDK4/6i in patients. Targeted sequencing of ctDNA via samples from PALOMA-3 also identified rare events in ERBB2 , AKT1 , KRAS , and FGFR2 which were both acquired and maintained at progression, however this analysis was limited by lack of insight into the clinical response phenotype of these samples.…”

Section: Discussionmentioning

confidence: 69%

“…This effort confirmed previous reports implicating rare events in RB1 while also revealing novel mediators of resistance including AKT1, RAS family oncogenes, AURKA, CCNE2, and ER loss. Prior work from our group and others identified mutational events in ERBB2 25 and the FGFR pathway 24, 26, 36 in driving resistance. In vitro experiments confirm that AKT1, KRAS G12D, AURKA, and CCNE2 confer resistance to CDK4/6i.…”

Section: Discussionmentioning

confidence: 87%

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

Wander

Cohen

Gong

et al. 2019

Preprint

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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.

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“…In the clinical setting, the postulated poor prognostic effect, likely to result from FGFR2/ER/PR-mediated resistance to endocrine therapies, was analyzed recently in advanced BCa patients, for whom activating genetic alterations in FGFR2 gene (mostly point mutations) were linked to resistance to anti-ER therapies [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. These studies, for the most part inconclusive, involved analyses of genetic alterations of different FGFs or FGFRs genes in metastatic BCa patients subjected to various intensive therapeutic regimens, including those with developed resistance to endocrine therapy.…”

Section: Introductionmentioning

confidence: 99%

Hormonal Receptor Status Determines Prognostic Significance of FGFR2 in Invasive Breast Carcinoma

Braun

Piasecka

Tomasik

et al. 2020

Cancers

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Interaction between fibroblast growth factor receptor 2 (FGFR2) and estrogen/progesterone receptors (ER/PR) affects resistance to anti-ER therapies, however the prognostic value of FGFR2 in breast cancer (BCa) remains largely unexplored. We have recently showed in vitro that FGFR2-mediated signaling alters PR activity and response to anti-ER treatment. Herein, prognostic significance of FGFR2 in BCa was evaluated in relation to both ER/PR protein status and a molecular signature designed to reflect PR transcriptional activity. FGFR2 was examined in 353 BCa cases using immunohistochemistry and Nanostring-based RNA quantification. FGFR2 expression was higher in ER+PR+ and ER+PR- compared to ER−PR− cases (p < 0.001). Low FGFR2 was associated with higher grade (p < 0.001), higher Ki67 proliferation index (p < 0.001), and worse overall and disease-free survival (HR = 2.34 (95% CI: 1.26–4.34), p = 0.007 and HR = 2.22 (95% CI: 1.25–3.93), p = 0.006, respectively). The poor prognostic value of low FGFR2 was apparent in ER+PR+, but not in ER+PR− patients, and it did not depend on the expression level of PR-dependent genes. Despite the functional link between FGFR2 and ER/PR revealed by preclinical studies, the data showed a link between FGFR2 expression and poor prognosis in BCa patients.

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FGFR1 Amplification Mediates Endocrine Resistance but Retains TORC Sensitivity in Metastatic Hormone Receptor–Positive (HR+) Breast Cancer

Cited by 61 publications

References 29 publications

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

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

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

Hormonal Receptor Status Determines Prognostic Significance of FGFR2 in Invasive Breast Carcinoma

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