TY - JOUR
T1 - Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer
AU - Punturi, Nindo B.
AU - Seker, Sinem
AU - Devarakonda, Vaishnavi
AU - Mazumder, Aloran
AU - Kalra, Rashi
AU - Chen, Ching Hui
AU - Li, Shunqiang
AU - Primeau, Tina
AU - Ellis, Matthew J.
AU - Kavuri, Shyam M.
AU - Haricharan, Svasti
N1 - Funding Information:
M.J.E. has intellectual property ownership and received royalties for the PAM50-based breast cancer test “Prosigna.” In the last 5 years he has received ad hoc consulting fees and meals (<$5000 per year) from Abbvie, Novartis, AstraZenica, Pfizer, Sermonix, and Puma. S.M.K. is a stakeholder in NeoZenome Therapeutics Inc. S.L. has received license fee from Envigo. He received research funding from Pfizer, Takeda Oncology, Zenopharm, NIH, and DOD, outside of this project. The other authors declare no competing interests.
Funding Information:
We would like to acknowledge the Patient-derived Xenograft and Advanced In Vivo Models core (funded by P30 Cancer Center Support Grant NCI-CA125123, CPRIT Core Facilities Support Grant RP170691) and Dr Michael T. Lewis, Ph.D., Academic Director, Lacey E. Dobrolecki, MS, Core Director at Baylor College of Medicine for helping us in engrafting WHIM20 PDX explants. We also thank Dr Alejandra Bruna (CRUK, UK) and Dr Violeta Serra (VHIO, Barcelona) for providing PDX drug response data and tumor sections for the STG and VHIO PDX lines. Work in this study was funded by Department of Defense Breast Cancer Research Program Breakthrough awards (W81XWH-18-1-0034 to S.H., W81XWH-18-1-0035 to S.M.K.), NCI K22 Career Development award (CA229613 to S.H.), Susan G. Komen Promise Grant (PG12220321 to M.J.E.), SPORE grant (P50CA186784-06), and Cancer Prevention and Research Institute of Texas (CPRIT) Recruitment of Established Investigators award (RR140033 to M.J.E.), National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), U24C196171.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Resistance to endocrine treatment occurs in ~30% of ER+ breast cancer patients resulting in ~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.
AB - Resistance to endocrine treatment occurs in ~30% of ER+ breast cancer patients resulting in ~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.
UR - http://www.scopus.com/inward/record.url?scp=85106321097&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-23271-0
DO - 10.1038/s41467-021-23271-0
M3 - Article
C2 - 34011995
AN - SCOPUS:85106321097
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2940
ER -