@article{a3b5069515774043a76014f609685991,
title = "Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity",
abstract = "Activating mutations in HER2 (ERBB2) drive the growth of a subset of breast and other cancers and tend to co-occur with HER3 (ERBB3) missense mutations. The HER2 tyrosine kinase inhibitor neratinib has shown clinical activity against HER2-mutant tumors. To characterize the role of HER3 mutations in HER2-mutant tumors, we integrate computational structural modeling with biochemical and cell biological analyses. Computational modeling predicts that the frequent HER3E928G kinase domain mutation enhances the affinity of HER2/HER3 and reduces binding of HER2 to its inhibitor neratinib. Co-expression of mutant HER2/HER3 enhances HER2/HER3 co-immunoprecipitation and ligand-independent activation of HER2/HER3 and PI3K/AKT, resulting in enhanced growth, invasiveness, and resistance to HER2-targeted therapies, which can be reversed by combined treatment with PI3Kα inhibitors. Our results provide a mechanistic rationale for the evolutionary selection of co-occurring HER2/HER3 mutations and the recent clinical observations that HER3 mutations are associated with a poor response to neratinib in HER2-mutant cancers.",
keywords = "HER2, HER3, PI3K, Rosetta, breast cancer, molecular dynamics, neratinib, personalized structural biology, precision oncology",
author = "Hanker, {Ariella B.} and Brown, {Benjamin P.} and Jens Meiler and Arnaldo Mar{\'i}n and Jayanthan, {Harikrishna S.} and Dan Ye and Lin, {Chang Ching} and Hiroaki Akamatsu and Lee, {Kyung Min} and Sumanta Chatterjee and Sudhan, {Dhivya R.} and Alberto Servetto and Brewer, {Monica Red} and Koch, {James P.} and Sheehan, {Jonathan H.} and Jie He and Lalani, {Alshad S.} and Arteaga, {Carlos L.}",
note = "Funding Information: We thank Ben Park for providing the MCF7 HER2 WT , HER2 L755S , and HER2 V777L isogenic cell lines, Samuel Aparicio for providing the SA493 breast cancer PDX, the UTSW Moody Foundation Flow Cytometry Facility, and members of the Arteaga and Meiler Laboratories and Christine Lovly for helpful discussions. This study was supported by NCI grant R01CA224899 (to A.B.H. and C.L.A.), the NCI/ UTSW Simmons Cancer Center P30 CA142543 , CPRIT RR170061 grant (to C.L.A.), NCI Breast SPORE grant P50 CA098131 , the NCI/ Vanderbilt-Ingram Cancer Center P30 CA68485 , the Susan G. Komen Breast Cancer Foundation grant SAB1800010 (to C.L.A.), and grants from the Breast Cancer Research Foundation (to A.B.H. and C.L.A.). B.P.B. is supported through the NIH by a Ruth L. Kirschstein NRSA fellowship ( F30DK118774 ). Funding Information: We thank Ben Park for providing the MCF7 HER2WT, HER2L755S, and HER2V777L isogenic cell lines, Samuel Aparicio for providing the SA493 breast cancer PDX, the UTSW Moody Foundation Flow Cytometry Facility, and members of the Arteaga and Meiler Laboratories and Christine Lovly for helpful discussions. This study was supported by NCI grant R01CA224899 (to A.B.H. and C.L.A.), the NCI/UTSW Simmons Cancer Center P30 CA142543, CPRIT RR170061 grant (to C.L.A.), NCI Breast SPORE grant P50 CA098131, the NCI/Vanderbilt-Ingram Cancer Center P30 CA68485, the Susan G. Komen Breast Cancer Foundation grant SAB1800010 (to C.L.A.), and grants from the Breast Cancer Research Foundation (to A.B.H. and C.L.A.). B.P.B. is supported through the NIH by a Ruth L. Kirschstein NRSA fellowship (F30DK118774). Conceptualization, A.B.H. J.M. and C.L.A.; methodology, A.B.H. B.P.B. H.S.J. A.M. D.Y. C.-C.L. K.-M.L. S.C. D.R.S. A.S. J.P.K. and J.H.S.; formal analysis, B.P.B.; investigation, A.B.H. B.P.B. A.M. D.Y. C.-C.L. H.A. K.-M.L. S.C. A.S. and J.P.K.; resources, D.Y. C.-C.L. S.C. D.R.S. M.R.B. J.H. and A.S.L.; data curation, A.B.H. B.P.B. and J.H.; writing ? original draft, A.B.H. B.P.B. and H.S.J.; writing ? review & editing, A.B.H. B.P.B. J.M. H.S.J. D.R.S. A.S. M.R.B. and C.L.A.; supervision, A.B.H. J.M. and C.L.A.; project management, A.B.H. J.M. and C.L.A.; funding acquisition, A.B.H. J.M. and C.L.A. A.B.H. receives or has received research grant support from Takeda and Lilly and travel support from Puma Biotechnology. J.H. is an employee of Foundation Medicine. A.S.L. is an employee of and holds ownership interest (including patents) in Puma Biotechnology, Inc. C.L.A. receives or has received research grant support from Pfizer, Lilly, Radius, Bayer, and Takeda, holds stock options in Provista, and serves or has served in a scientific advisory role to Puma Biotechnology, Novartis, Lilly, TAIHO Oncology, Daiichi Sankyo, Merck, AstraZeneca, OrigiMed, Immunomedics, Athenex, Arvinas, and the Susan G. Komen Foundation. All other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = aug,
day = "9",
doi = "10.1016/j.ccell.2021.06.001",
language = "English (US)",
volume = "39",
pages = "1099--1114.e8",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "8",
}