PT  - JOURNAL ARTICLE
AU  - Ngan, Hoi-Lam
AU  - Liu, Yuchen
AU  - Fong, Andrew Yuon
AU  - Poon, Peony Hiu Yan
AU  - Yeung, Chun Kit
AU  - Chan, Sharon Suet Man
AU  - Lau, Alexandria
AU  - Piao, Wenying
AU  - Li, Hui
AU  - Tse, Jessie Sze Wing
AU  - Lo, Kwok-Wai
AU  - Chan, Sze Man
AU  - Su, Yu-Xiong
AU  - Chan, Jason Ying Kuen
AU  - Lau, Chin Wang
AU  - Mills, Gordon B
AU  - Grandis, Jennifer Rubin
AU  - Lui, Vivian Wai Yan
TI  - MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling
AID  - 10.26508/lsa.201900545
DP  - 2020 Jun 01
TA  - Life Science Alliance
PG  - e201900545
VI  - 3
IP  - 6
4099  - http://www.life-science-alliance.org/content/3/6/e201900545.short
4100  - http://www.life-science-alliance.org/content/3/6/e201900545.full
SO  - Life Sci. Alliance2020 Jun 01; 3
AB  - MAPK pathway mutations affect one-fifth of head and neck squamous cell carcinoma (HNSCC). Unexpectedly, MAPK pathway aberrations are associated with remarkably long patient survival, even among patients with TP53 mutations (median ∼14 yr). We explored underlying outcome-favoring mechanisms with omics followed by preclinical models. Strikingly, multiple hotspot and non-hotspot MAPK mutations (A/BRAF, HRAS, MAPK1, and MAP2K1/2) all abrogated ErbB3 activation, a well-established HNSCC progression signal. Inhibitor studies functionally defined ERK activity negatively regulating phospho-ErbB3 in MAPK-mutants. Furthermore, pan-pathway immunoprofiling investigations identified MAPK-mutant tumors as the only “CD8+ T-cell–inflamed” tumors inherently bearing high-immunoreactive, constitutive cytolytic tumor microenvironments. Immunocompetent MAPK-mutant HNSCC models displayed active cell death and massive CD8+ T-cell recruitment in situ. Consistent with CD8+ T-inflamed phenotypes, MAPK-mutant HNSCC patients, independent of tumor-mutational burden, survived 3.3–4 times longer than WT patients with anti-PD1/PD-L1 immunotherapies. Similar prognosticity was noted in pan-cancers. We uncovered clinical, signaling, and immunological uniqueness of MAPK-mutant HNSCC with potential biomarker utilities predicting favorable patient survival.