Loss of Mismatch Repair Predicts Resistance to Endocrine Therapy and Sensitivity to CDK4/6 Inhibitors in ER-Positive Breast Cancer

Estrogen receptor (ER)-positive breast cancer is treated with endocrine therapy but intrinsic resistance occurs in approximately one-third of patients and acquired resistance in approximately one-fifth of the remainder.¹ Although many resistance mechanisms have been explored, clinical trials testing associated therapeutics have had mixed outcomes. Therefore, understanding mechanisms of resistance and finding therapeutic strategies to target them remain important challenges.

In the study presented at SABCS 2017, the authors discovered an intriguing link between mismatch repair (MMR) deficiency, specifically of the MutL complex (MLH1/3, PMS1/2), and endocrine therapy resistance in ER-positive disease.² They found a direct role for MutL loss in inducing endocrine therapy resistance in vitro and in vivo by knocking down multiple MutL genes using CRISPR and stable shRNA approaches that were validated using standard rescue experiments. They identified the underlying mechanism—that MutL deficiency in ER-positive breast cancer abrogates Chk2-mediated feedback inhibition of CDK4/6 that appears necessary for endocrine therapy responsiveness. Consequently, pharmacologic targeting of CDK4/6 in vitro and in vivo significantly inhibits the growth of endocrine therapy–resistant, MutL-deficient, ER-positive breast cancer cells.

These results are corroborated by data from a neoadjuvant clinical trial demonstrating that cell-cycle regulation of MutL-mutant tumors is estrogen-independent but CDK4/6-dependent.³ The results of this study provide important biological and clinically relevant insights: (1) a novel role for MMR in endocrine therapy resistance, and (2) a mechanism underlying the effectiveness of CDK4/6 inhibitors in some de novo endocrine therapy–resistant tumors. Although there are currently no biomarkers to guide the use of CDK4/6 inhibitors for ER-positive breast cancer, markers of MMR dysregulation could identify patients in whom CDK4/6 inhibition may prevent disease recurrence most effectively.

References

1. Araki K, Miyoshi Y. Breast Cancer. 2017 Oct 31. doi: 10.1007/s12282-017-0812-x. Epub ahead of print.
2. Haricharan S, et al. SABCS 2017. Abstract P4-04-01.
3. Haricharan S, et al. Cancer Discov. 2017;7:1168-1183.