Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer

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 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 AI-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 breast cancer patients who exhibit marked resistance to the current standard of care.

Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer

“…All arms were deprived of estrogen supplementation at randomization. As expected from previous experiments 15 , we observed estrogen independent and fulvestrant resistant growth in MCF7 shMLH1 tumors, and little response to lapatinib alone ( Fig 4A). However, there was striking response with tumor shrinkage to the combination of fulvestrant and lapatinib ( Fig 4A).…”

“…Since MutL -ER + tumors have a higher mutation load than MutL + tumors 15,19 we tested whether HER2 activation in these tumors occurred via activating mutations 11 . However, frequency of HER2 mutations did not significantly associate with MutL status, if anything appearing lower in MutL -ER + tumors than in MutL + ones ( Fig S2C).…”

“…Stable cell lines were maintained in presence of specified antibiotics at recommended concentrations. Growth assays were conducted in triplicate and repeated independently as previously using Alamar blue to identify cell viability 15 . Growth assay results were plotted as fold change in growth from days 1 to 7 and normalized as specified.…”

“…Defects in the MutL complex of mismatch repair, comprised of MLH1 and PMS2, were recently identified as drivers of endocrine treatment resistance in 15-17% of ER + /HER2breast cancer patients 15,16 . Mismatch repair is a fundamental DNA repair pathway conserved between pro-and eukaryotes, and essential for guarding the genome during cellular replication 17 .…”

The prognostic effects of somatic mutations in ER-positive breast cancer

“…Mutations in PRKDC will potentially produce a defective ATM response/low ATM levels 27 which is interesting in the context of the finding herein that ATM mutations are a potential luminal B driver gene. The significance of a defective ATM pathway as a cause of endocrine resistance is highlighted by the recent finding that dysregulation of the MutL complex (MLH1, PMS1 and PMS2) causes failure of ATM/CHK2-based negative regulation of CDK4/6 28 . Prognostic candidate mutations revealed by the MA12 analysis were different from the UBC TAM series, likely reflecting the different patient profiles and adjuvant treatments illustrated in Figure 2 .…”