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Ref Type Journal Article
PMID (31594766)
Authors Costa C, Wang Y, Ly A, Hosono Y, Murchie E, Walmsley CS, Huynh T, Healy C, Peterson R, Yanase S, Jakubik CT, Henderson LE, Damon LJ, Timonina D, Sanidas I, Pinto CJ, Mino-Kenudson M, Stone JR, Dyson NJ, Ellisen LW, Bardia A, Ebi H, Benes CH, Engelman JA, Juric D
Title PTEN Loss Mediates Clinical Cross-Resistance to CDK4/6 and PI3Kα Inhibitors in Breast Cancer.
Journal Cancer discovery
Vol 10
Issue 1
Date 2020 Jan
URL
Abstract Text The combination of CDK4/6 inhibitors with antiestrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of PTEN, through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo. Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because PTEN loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment-sequencing strategies. SIGNIFICANCE: Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as first-line treatment for ER-positive advanced breast cancer. Importantly, these findings have near-term clinical relevance because PTEN loss also limits the efficacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting.This article is highlighted in the In This Issue feature, p. 1.

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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 breast cancer sensitive Fulvestrant + MK2206 + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the combination of Ibrance (palbociclib), Faslodex (fulvestrant), and MK2206 inhibited growth of PTEN-deficient breast cancer cells in culture (PMID: 31594766). 31594766
PTEN loss breast cancer decreased response Palbociclib Preclinical - Cell culture Actionable In a preclinical study, two PTEN-deficient breast cancer cell lines demonstrated a decreased response to treatment with Ibrance (palbociclib) compared to control cells in culture (PMID: 31594766). 31594766
PTEN loss breast cancer sensitive MK2206 + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the combination treatment of MK2206 and Kisqali (ribociclib) induced cell cycle arrest and inhibited cell proliferation of PTEN-deficient breast cancer cells in culture and led to tumor regression in cell-line xenograft models (PMID: 31594766). 31594766
PTEN loss breast cancer resistant Fulvestrant + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, PTEN-deficient breast cancer cells demonstrated resistance to the combination of Kisqali (ribociclib) and Faslodex (fulvestrant) in culture (PMID: 31594766). 31594766
PTEN loss breast cancer sensitive Ipatasertib + Palbociclib Preclinical - Cell culture Actionable In a preclinical study, the combination of Ibrance (palbociclib) and Ipatasertib (GDC-0068) inhibited growth of PTEN-deficient breast cancer cells in culture (PMID: 31594766). 31594766
PTEN loss breast cancer sensitive Ipatasertib + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the combination of Ipatasertib (GDC-0068) and Kisqali (ribociclib) induced cell cycle arrest and inhibited growth of PTEN-deficient breast cancer cells in culture (PMID: 31594766). 31594766
PTEN loss breast cancer predicted - resistant Ribociclib Preclinical - Cell culture Actionable In a preclinical study, treatment with Kisqali (ribociclib) resulted in a decreased response in two PTEN-deficient breast cancer cell lines in culture compared to control cells and resistance in a cell-line xenograft model (PMID: 31594766). 31594766
PTEN loss breast cancer sensitive MK2206 + Palbociclib Preclinical - Cell culture Actionable In a preclinical study, the combination of Ibrance (palbociclib) and MK2206 inhibited growth of PTEN-deficient breast cancer cells in culture (PMID: 31594766). 31594766