Reference Detail

Ref Type

Journal Article

PMID

(27020857)

Authors

Herrera-Abreu MT, Palafox M, Asghar U, Rivas MA, Cutts RJ, Garcia-Murillas I, Pearson A, Guzman M, Rodriguez O, Grueso J, Bellet M, Cortés J, Elliott R, Pancholi S, Baselga J, Dowsett M, Martin LA, Turner NC, Serra V

Title

Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor-Positive Breast Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	76	8	2016 04 15	2301-13	Cancer Res

URL

Abstract Text

Small-molecule inhibitors of the CDK4/6 cell-cycle kinases have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer, although their cytostatic effects are limited by primary and acquired resistance. Here we report that ER-positive breast cancer cells can adapt quickly to CDK4/6 inhibition and evade cytostasis, in part, via noncanonical cyclin D1-CDK2-mediated S-phase entry. This adaptation was prevented by cotreatment with hormone therapies or PI3K inhibitors, which reduced the levels of cyclin D1 (CCND1) and other G1-S cyclins, abolished pRb phosphorylation, and inhibited activation of S-phase transcriptional programs. Combined targeting of both CDK4/6 and PI3K triggered cancer cell apoptosis in vitro and in patient-derived tumor xenograft (PDX) models, resulting in tumor regression and improved disease control. Furthermore, a triple combination of endocrine therapy, CDK4/6, and PI3K inhibition was more effective than paired combinations, provoking rapid tumor regressions in a PDX model. Mechanistic investigations showed that acquired resistance to CDK4/6 inhibition resulted from bypass of cyclin D1-CDK4/6 dependency through selection of CCNE1 amplification or RB1 loss. Notably, although PI3K inhibitors could prevent resistance to CDK4/6 inhibitors, they failed to resensitize cells once resistance had been acquired. However, we found that cells acquiring resistance to CDK4/6 inhibitors due to CCNE1 amplification could be resensitized by targeting CDK2. Overall, our results illustrate convergent mechanisms of early adaptation and acquired resistance to CDK4/6 inhibitors that enable alternate means of S-phase entry, highlighting strategies to prevent the acquisition of therapeutic resistance to these agents. Cancer Res; 76(8); 2301-13. ©2016 AACR.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN loss RB1 loss	triple-receptor negative breast cancer	no benefit	Palbociclib + Pictilisib	Preclinical	Actionable	In a preclinical study, the combination of Ibrance (palbociclib) and Pictilisib (GDC-0941) did not improve growth inhibition compared to single drug treatment in triple-receptor negative breast cancer cell lines harboring PTEN and RB1 loss in culture (PMID: 27020857).	27020857
RB1 loss	estrogen-receptor positive breast cancer	resistant	Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, RB1 loss was associated with acquired resistance to Ibrance (palbociclib) in an estrogen-receptor positive breast cancer cell line in culture (PMID: 27020857).	27020857
PTEN loss RB1 loss	triple-receptor negative breast cancer	resistant	Pictilisib	Preclinical	Actionable	In a preclinical study, a triple-receptor negative breast cancer line harboring PTEN and RB1 loss was resistant to Pictilisib (GDC-0941) induced growth inhibition in culture (PMID: 27020857).	27020857
PIK3CA mutant	triple-receptor negative breast cancer	sensitive	Palbociclib + Pictilisib	Preclinical	Actionable	In a preclinical study, Ibrance (palbociclib) and Pictilisib (GDC-0941) worked synergistically to inhibit the survival of triple-receptor negative breast cancer cell lines harboring PIK3CA mutations in culture (PMID: 27020857).	27020857
PTEN loss RB1 loss	triple-receptor negative breast cancer	resistant	Palbociclib	Preclinical	Actionable	In a preclinical study, a triple-receptor negative breast cancer line harboring PTEN and RB1 loss was resistant to Ibrance (palbociclib) induced growth inhibition in culture (PMID: 27020857).	27020857
PIK3CA wild-type	triple-receptor negative breast cancer	no benefit	Palbociclib + Pictilisib	Preclinical	Actionable	In a preclinical study, the combination of Ibrance (palbociclib) and Pictilisib (GDC-0941) did not improve growth inhibition compared to single drug treatment in PIK3CA wild-type, triple-receptor negative breast cancer cell lines in culture (PMID: 27020857).	27020857