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. Cancer Discov; 7(10); 1–16. ©2017 AACR.

≥20％的雌激素受体阳性（ER ⁺）原发性乳腺癌中存在明显的内分泌治疗耐药性肿瘤增殖，并与疾病复发和死亡相关。在这里，我们发现内在内分泌治疗耐药性与MutL错配修复（MMR）复合物（MLH1 / 3，PMS1 / 2）失调之间的联系，并证明MutL复合物丧失对所有类型的内分泌治疗均具有直接作用。我们发现，ER ⁺乳腺癌中的MutL缺乏消除了CHK2介导的CDK4抑制，CDK4是内分泌治疗反应性的先决条件。因此，CDK4 / 6抑制剂（CDK4 / 6i）在MutL缺陷型ER ^+中仍然有效乳腺癌细胞。这些观察结果得到了一项临床试验数据的支持，该临床试验发现CDK4 / 6i可以强烈抑制MutL缺陷肿瘤对芳香化酶抑制剂的抗性增殖。这些数据表明，MutL缺乏症的诊断标记物可用于将佐剂CDK4 / 6i引向对当前护理标准表现出明显抵抗力的乳腺癌患者人群。

重要性：一部分ER ⁺原发性肿瘤中的MutL缺乏解释了为什么CDK4 / 6抑制作用可以有效地抵抗某些从头对内分泌治疗的肿瘤。因此，MutL失调的标记物可以指导CDK4 / 6抑制剂在佐剂环境中的使用，在这种情况下，非靶向治疗干预的风险获益比很窄。巨蟹座Discov; 7（10）；1–16。©2017 AACR。