Journal
CANCER DISCOVERY
Volume 7, Issue 10, Pages 1168-1183Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-16-1179
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Funding
- Susan G. Komen Promise Grant [PG12220321]
- Cancer Prevention and Research Institute of Texas (CPRIT) Recruitment of Established Investigators Award [RR140033]
- Laura Ziskin Award from Stand Up To Cancer [R01 CA095614]
- Komen CCR award [CCR16380599]
- NCI of the NIH [U10CA180821, U10CA180882, U10CA077440, U10CA180833, U10CA180858]
- Pfizer Pharmaceuticals
- Siteman Cancer Center Grant [P30 CA91842]
- NCI Cancer Clinical Investigator Team Leadership Award [3P30 CA091842-12S2]
- Susan G. Komen Promise Grant
- Saint Louis Men's Group Against Cancer
- CPRIT Proteomics & Metabolomics Core Facility Support Award [RP120092]
- NCI Cancer Center Support Grant [P30CA125123]
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Significant endocrine therapy-resistant tumor proliferation is present in = 20% of estrogen receptor-positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER + breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER + breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor-resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care. SIGNIFICANCE: MutL deficiency in a subset of ER + primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy-resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. (C) 2017 AACR.
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