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

被引：17

作者：

Punturi, Nindo B. ^{[1
]}

Seker, Sinem ^{[1
]}

Devarakonda, Vaishnavi ^{[2
,3
]}

Mazumder, Aloran ^{[1
]}

Kalra, Rashi ^{[2
,3
]}

Chen, Ching Hui ^{[2
,3
]}

Li, Shunqiang ^{[4
]}

Primeau, Tina ^{[4
]}

Ellis, Matthew J. ^{[2
,3
]}

Kavuri, Shyam M. ^{[2
,3
]}

Haricharan, Svasti ^{[1
]}

机构：

[1] Sanford Burnham Prebys Med Discovery Inst, Tumor Microenvironm & Canc Immunol, La Jolla, CA 92037 USA

[2] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA

[3] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

[4] Washington Univ, Dept Med, St Louis, MO USA

来源：

NATURE COMMUNICATIONS | 2021年 / 12卷 / 01期

基金：

美国国家卫生研究院;

关键词：

GROWTH-FACTOR RECEPTOR; ESTROGEN-RECEPTOR; POSTMENOPAUSAL WOMEN; ENDOCRINE THERAPY; INHIBITOR; LAPATINIB; EXPRESSION; TRIAL; ER; CHEMOTHERAPY;

D O I：

10.1038/s41467-021-23271-0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Resistance to endocrine treatment occurs in similar to 30% of ER+ breast cancer patients resulting in similar to 40,000 deaths/year in the USA. Preclinical studies strongly implicate activation of growth factor receptor, HER2 in endocrine treatment resistance. However, clinical trials of pan-HER inhibitors in ER+/HER2(-) patients have disappointed, likely due to a lack of predictive biomarkers. Here we demonstrate that loss of mismatch repair activates HER2 after endocrine treatment in ER+/HER2(-) breast cancer cells by protecting HER2 from protein trafficking. Additionally, HER2 activation is indispensable for endocrine treatment resistance in MutL(-) cells. Consequently, inhibiting HER2 restores sensitivity to endocrine treatment. Patient data from multiple clinical datasets supports an association between MutL loss, HER2 upregulation, and sensitivity to HER inhibitors in ER+/HER2(-) patients. These results provide strong rationale for MutL loss as a first-in-class predictive marker of sensitivity to combinatorial treatment with endocrine intervention and HER inhibitors in endocrine treatment-resistant ER+/HER2(-) breast cancer patients.

引用

页数：11

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