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Ref Type Journal Article
PMID (26977878)
Authors Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, Ramm S, Palmer AC, Yuzugullu H, Varadan V, Tuck D, Harris LN, Wong KK, Liu XS, Sicinski P, Winer EP, Krop IE, Zhao JJ
Title Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors.
Journal Cancer cell
Vol 29
Issue 3
Date 2016 Mar 14
URL
Abstract Text Using transgenic mouse models, cell line-based functional studies, and clinical specimens, we show that cyclin D1/CDK4 mediate resistance to targeted therapy for HER2-positive breast cancer. This is overcome using CDK4/6 inhibitors. Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC1 activity. This relieves feedback inhibition of upstream EGFR family kinases, resensitizing tumors to EGFR/HER2 blockade. Consequently, dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of TSC2 phosphorylation and hence mTORC1/S6K/S6RP activity. The suppression of both Rb and S6RP enhances G1 arrest and a phenotype resembling cellular senescence. In vivo, CDK4/6 inhibitors sensitize patient-derived xenograft tumors to HER2-targeted therapies and delay tumor recurrence in a transgenic model of HER2-positive breast cancer.

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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
Unknown unknown Her2-receptor positive breast cancer not applicable Abemaciclib + Trastuzumab Preclinical - Pdx & cell culture Actionable In a preclinical study, the combination of Herceptin (trastuzumab) and Abemaciclib (LY2835219) resulted in tumor growth regresssion in an ERBB2 (HER2)-receptor positive breast cancer treatment refractory patient derived xenograft model and in ERBB2 (HER2)-receptor positive cultured cells, resulted in decreased cell viability (PMID: 26977878). 26977878
Unknown unknown Her2-receptor positive breast cancer not applicable Abemaciclib Preclinical - Pdx & cell culture Actionable In a preclinical study, an ERBB2 (HER2)-receptor positive breast cancer cell line xenograft model treated with Abemaciclib (LY2835219) demonstrated delayed tumor growth and in culture, resulted in some decreased cell viability (PMID: 26977878). 26977878
Unknown unknown Her2-receptor positive breast cancer not applicable Abemaciclib + Lapatinib Preclinical - Cell culture Actionable In a preclinical study, the addition of Abemaciclib (LY2835219) to Tykerb (lapatinib) treatment enhanced growth inhibitory effects of Tykerb (lapatinib)-resistant ERBB2 (HER2)-receptor positive breast cancer cells in culture (PMID: 26977878). 26977878