Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer

Formisano, Luigi; Lu, Yao; Servetto, Alberto; Hanker, Ariella B.; Jansen, Valerie M.; Bauer, Joshua A.; Sudhan, Dhivya R.; Guerrero-Zotano, Ángel; Croessmann, Sarah; Guo, Yan; Gonzalez-Ericsson, Paula I.; Lee, Kyung-min; Nixon, Mellissa J.; Schwarz, Luis J.; Sanders, Melinda E.; Dugger, Teresa C.; Cruz, Marcelo; Behdad, Amir; Cristofanilli, Massimo; Bardia, Aditya; O’Shaughnessy, Joyce; Nagy, Rebecca J.; Lanman, Richard B.; Solovieff, Nadia; He, Wei; Miller, Michelle C.; Su, Fei; Shyr, Yu; Mayer, Ingrid A.; Balko, Justin M.; Arteaga, Carlos L.

doi:10.1038/s41467-019-09068-2

Cited by 301 publications

(283 citation statements)

References 57 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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“…21 Breast cancer with CCND1/FGFR1 mutated clone will benefit of combined erdafitinib plus ribociclib and fulvestrant. 22 In the majority of cases, the second cfDNA analysis confirmed the clone identified in the first analysis ( Figure 3). However, not 100% of mutated clones were still present at the second liquid biopsy.…”

Section: Discussionsupporting

confidence: 53%

“…For example gastric cancer with growing TP53 / ERBB2 mutated clone will benefit of Transtuzumab plus chemotherapy . Breast cancer with CCND1 / FGFR1 mutated clone will benefit of combined erdafitinib plus ribociclib and fulvestrant …”

Section: Discussionmentioning

confidence: 99%

Two‐point‐NGS analysis of cancer genes in cell‐free DNA of metastatic cancer patients

et al. 2020

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Background Although the efficacy of molecularly target agents in vitro, their use in routine setting is limited mainly to the use of anti‐HER2 and antiEGFR agents in vivo. Moreover, core biopsy of a single cancer site may not be representative of the whole expanding clones and cancer molecular profile at relapse may differ with respect to the primary tumor. Methods We assessed the status of a large panel of cancer driver genes by cell‐free DNA (cfDNA) analysis in a cohort of 68 patients with 13 different solid tumors at disease progression. Whenever possible, a second cfDNA analysis was performed after a mean of 2.5 months, in order to confirm the identified clone(s) and to check the correlation with clinical evolution. Results The approach was able to identify clones plausibly involved in the disease progression mechanism in about 65% of cases. A mean of 1.4 mutated genes (range 1‐3) for each tumor was found. Point mutations in TP53, PIK3CA, and KRAS and copy number variations in FGFR3 were the gene alterations more commonly observed, with a rate of 48%, 20%, 16%, and 20%, respectively. Two‐points‐Next‐Generation Sequencing (NGS) analysis demonstrated statistically significant correlation between allele frequency variation and clinical outcome (P = .026). Conclusions Irrespective of the primary tumor mutational burden, few mutated genes are present at disease progression. Clinical outcome is consistent with variation of allele frequency of specific clones indicating that cfDNA two‐point‐NGS analysis of cancer driver genes could be an efficacy tool for precision oncology.

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“…24, 25 In addition, amplification of FGFR1 , identified via sequencing of ctDNA from MONALEESA-2 (ribociclib and anti-estrogen in the first-line metastatic setting), correlated with reduced PFS and activation of FGFR1 provoked resistance in vitro. 26…”

Section: Introductionmentioning

confidence: 99%

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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Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer

Cited by 301 publications

References 57 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

Two‐point‐NGS analysis of cancer genes in cell‐free DNA of metastatic cancer patients

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

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