Loss of mutl disrupts CHK2-dependent cell-cycle control through CDK4/6 to promote intrinsic endocrine therapy resistance in primary breast cancer

Svasti Haricharan, Nindo Punturi, Purba Singh, Kimberly R. Holloway, Meenakshi Anurag, Jacob Schmelz, Cheryl Schmidt, Jonathan T. Lei, Vera Suman, Kelly Hunt, John A. Olson, Jeremy Hoog, Shunqiang Li, Shixia Huang, Dean P. Edwards, Shyam M. Kavuri, Matthew N. Bainbridge, Cynthia X. Ma, Matthew J. Ellis

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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 defi ciency 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 benefi t ratio for untargeted therapeutic intervention is narrow.

Original languageEnglish
Pages (from-to)1168-1183
Number of pages16
JournalCancer discovery
Volume7
Issue number10
DOIs
StatePublished - Oct 2017

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    Haricharan, S., Punturi, N., Singh, P., Holloway, K. R., Anurag, M., Schmelz, J., Schmidt, C., Lei, J. T., Suman, V., Hunt, K., Olson, J. A., Hoog, J., Li, S., Huang, S., Edwards, D. P., Kavuri, S. M., Bainbridge, M. N., Ma, C. X., & Ellis, M. J. (2017). Loss of mutl disrupts CHK2-dependent cell-cycle control through CDK4/6 to promote intrinsic endocrine therapy resistance in primary breast cancer. Cancer discovery, 7(10), 1168-1183. https://doi.org/10.1158/2159-8290.CD-16-1179