Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer.
Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer.
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DOI：
10.1158/2159-8290.cd-16-1179
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发表时间：
2017-10
期刊：
影响因子：
28.2
通讯作者：
Ellis MJ
中科院分区：
文献类型：
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作者：
Haricharan S;Punturi N;Singh P;Holloway KR;Anurag M;Schmelz J;Schmidt C;Lei JT;Suman V;Hunt K;Olson JA Jr;Hoog J;Li S;Huang S;Edwards DP;Kavuri SM;Bainbridge MN;Ma CX;Ellis MJ
≥20%的雌激素受体阳性（ER+）原发性乳腺癌存在显著的内分泌治疗抵抗性肿瘤增殖，并与疾病复发和死亡相关。在这里，我们揭示了内在内分泌治疗抵抗和MutL错配修复复合体（MLH1/3, PMS1/2）失调之间的联系，并证明了MutL复合体的丧失在对所有内分泌治疗的抵抗中起直接作用。我们发现，在ER+乳腺癌中，MutL缺乏会消除chk2介导的CDK4抑制，而CDK4抑制是内分泌治疗反应性的先决条件。因此，CDK4/6抑制剂（CDK4/6i）在多缺陷ER+乳腺癌细胞中仍然有效。这些观察结果得到了一项临床试验数据的支持，该试验发现CDK4/6i强烈抑制多缺陷肿瘤的ai抗性增殖。这些数据表明，MutL缺乏症的诊断标记物可用于将辅助CDK4/6i直接用于对当前标准治疗表现出明显耐药性的乳腺癌患者群体。
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.