Abstract 1008: Gain-of-function kinase library screen identifies FGFR1 amplification as a mechanism of resistance to antiestrogens and CDK4/6 inhibitors in ER+ breast cancer

Formisano, Luigi; Lu, Yao; Jansen, Valerie M.; Bauer, Joshua A.; Hanker, Ariella B.; Sanders, Melinda E.; González-Ericsson, Paula I.; Kim, Sunkyu; Arnedos, Mónica; André, Fabrice; Arteaga, Carlos L.

doi:10.1158/1538-7445.am2017-1008

Cited by 12 publications

(7 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The failure of these cells to undergo senescence may facilitate escape via upregulation of an RTK-dependent pathway. FGFR-mediated pathways may be relevant not only to NSCLC cells but also to breast cancer cells with acquired palbociclib resistance [ 43 ]. Conversely, however, high baseline activation of an RTK-dependent pathway (e.g.…”

Section: Discussionmentioning

confidence: 99%

Palbociclib resistance confers dependence on an FGFR-MAP kinase-mTOR-driven pathway inKRAS-mutant non-small cell lung cancer

et al. 2018

View full text Add to dashboard Cite

CDK4 is emerging as a target in KRAS-mutant non-small cell lung cancer (NSCLC). We demonstrate that KRAS-mutant NSCLC cell lines are initially sensitive to the CDK4/6 inhibitor palbociclib, but readily acquire resistance associated with increased expression of CDK6, D-type cyclins and cyclin E. Resistant cells also demonstrated increased ERK1/2 activity and sensitivity to MEK and ERK inhibitors. Moreover, MEK inhibition reduced the expression and activity of cell cycle proteins mediating palbociclib resistance. In resistant cells, ERK activated mTOR, driven in part by upstream FGFR1 signaling resulting from the extracellular secretion of FGF ligands. A genetically-engineered mouse model of KRAS-mutant NSCLC initially sensitive to palbociclib similarly developed acquired resistance with increased expression of cell cycle mediators, ERK1/2 and FGFR1. In this model, resistance was delayed with combined palbociclib and MEK inhibitor treatment. These findings implicate an FGFR1–MAP kinase–mTOR pathway resulting in increased expression of D-cyclins and CDK6 that confers palbociclib resistance and indicate that CDK4/6 inhibition acts to promote MAP kinase dependence.

show abstract

Section: Discussionmentioning

confidence: 99%

Palbociclib resistance confers dependence on an FGFR-MAP kinase-mTOR-driven pathway inKRAS-mutant non-small cell lung cancer

et al. 2018

View full text Add to dashboard Cite

show abstract

“…A variety of approaches including functional genomics, pharmacogenomics and comparative phenotypic analyses of innately sensitive and resistant models, and characterization of breast cancer cell lines with acquired CDK4/6 inhibitor resistance have been used. Such studies have revealed a number of candidate mechanisms including: upregulated AKT signaling [48][49][50], deregulated expression of Cyclin E-CDK2 and CCNE1 DNA amplification [48,49,51], acquired RB1 inactivating mutations [48,52], FGFR1 amplification or activating FGFR2 mutations [53,54], and upregulation of PDK1, MYC, or SKP2 [49,55] ( Figure 2(b)). However, it remains to be seen whether these mechanisms identified in vitro will be clinically relevant in drug-treated patients.…”

Section: Targeting the Cell Cycle In Er+ Breast Cancer: Cdk4/6 Inhibimentioning

confidence: 99%

Targeting the cell cycle in breast cancer: towards the next phase

et al. 2018

View full text Add to dashboard Cite

Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Consequently, therapeutic targeting of the cell cycle has long been viewed as a promising anti-cancer strategy. Until recently, attempts to target the cell cycle for cancer therapy using selective inhibitors have proven unsuccessful due to intolerable toxicities and a lack of target specificity. However, improvements in our understanding of malignant cell-specific vulnerabilities has revealed a therapeutic window for preferential targeting of the cell cycle in cancer cells, and has led to the development of agents now in the clinic. In this review, we discuss the latest generation of cell cycle targeting anti-cancer agents for breast cancer, including approved CDK4/6 inhibitors, and investigational TTK and PLK4 inhibitors that are currently in clinical trials. In recognition of the emerging population of ER+ breast cancers with acquired resistance to CDK4/6 inhibitors we suggest new therapeutic avenues to treat these patients. We also offer our perspective on the direction of future research to address the problem of drug resistance, and discuss the mechanistic insights required for the successful implementation of these strategies.

show abstract

“…These findings are consistent with our data showing that differential Akt signaling was modulated by the ERα and XPO1 crosstalk. Of note, 4-OHT+SEL reduced targets of FGFR1 signaling, recently shown to be associated with Palbociclib + Fulvestrant-resistant tumors [40,41]. Overall, our gene expression analysis showed that the 4-OHT+SEL treatment was very effective in downregulating genes associated with endocrine resistance and metastasis.…”

Section: Resultsmentioning

confidence: 51%

Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance

Kulkoyluoglu-Cotul

Smith

Wrobel

et al. 2019

Cancers

View full text Add to dashboard Cite

A majority of breast cancer specific deaths in women with ERα (+) tumors occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and the nuclear transport protein XPO1 in overcoming endocrine resistance. Selinexor (SEL), an XPO1 antagonist, has been evaluated in multiple late stage clinical trials in patients with relapsed and /or refractory hematological and solid tumor malignancies. Our transcriptomics analysis showed that 4-Hydroxytamoxifen (4-OHT), SEL alone or their combination induced differential Akt signaling- and metabolism-associated gene expression profiles. Western blot analysis in endocrine resistant cell lines and xenograft models validated differential Akt phosphorylation. Using the Seahorse metabolic profiler, we showed that ERα-XPO1 targeting changed the metabolic phenotype of TAM-resistant breast cancer cells from an energetic to a quiescent profile. This finding demonstrated that combined targeting of XPO1 and ERα rewired the metabolic pathways and shut down both glycolytic and mitochondrial pathways that would eventually lead to autophagy. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and given the need for better strategies to improve therapy response in relapsed ERα (+) tumors, our findings show great promise for uncovering the role that ERα-XPO1 crosstalk plays in reducing cancer recurrences.

show abstract

Abstract 1008: Gain-of-function kinase library screen identifies FGFR1 amplification as a mechanism of resistance to antiestrogens and CDK4/6 inhibitors in ER+ breast cancer

Cited by 12 publications

References 0 publications

Palbociclib resistance confers dependence on an FGFR-MAP kinase-mTOR-driven pathway inKRAS-mutant non-small cell lung cancer

Palbociclib resistance confers dependence on an FGFR-MAP kinase-mTOR-driven pathway inKRAS-mutant non-small cell lung cancer

Targeting the cell cycle in breast cancer: towards the next phase

Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance

Contact Info

Product

Resources

About