Journal Article
. 2020 May; 3(6):.
doi: 10.26508/lsa.201900545.

MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling

Hoi-Lam Ngan 1 Yuchen Liu 1 Andrew Yuon Fong 2 Peony Hiu Yan Poon 1 Chun Kit Yeung 1 Sharon Suet Man Chan 3 Alexandria Lau 1 Wenying Piao 1 Hui Li 1 Jessie Sze Wing Tse 1 Kwok-Wai Lo 4 Sze Man Chan 1 Yu-Xiong Su 5 Jason Ying Kuen Chan 6 Chin Wang Lau 7 Gordon B Mills 8 Jennifer Rubin Grandis 9 Vivian Wai Yan Lui 10 
  • PMID: 32381551
  •     36 References
  •     4 citations


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.

Genomic Correlate of Exceptional Erlotinib Response in Head and Neck Squamous Cell Carcinoma.
Eliezer M Van Allen, Vivian W Y Lui, +24 authors, Jennifer R Grandis.
JAMA Oncol, 2015 Jul 17; 1(2). PMID: 26181029    Free PMC article.
ERBB3/HER2 signaling promotes resistance to EGFR blockade in head and neck and colorectal cancer models.
Li Zhang, Carla Castanaro, +15 authors, Christopher Daly.
Mol Cancer Ther, 2014 Mar 19; 13(5). PMID: 24634416
The role of c-erbB receptors and ligands in head and neck squamous cell carcinoma.
Pornchai O-charoenrat, Peter H Rhys-Evans, Helmout Modjtahedi, Suzanne A Eccles.
Oral Oncol, 2002 Aug 09; 38(7). PMID: 12167415
Tumor-infiltrating BRAFV600E-specific CD4+ T cells correlated with complete clinical response in melanoma.
Joshua R Veatch, Sylvia M Lee, +10 authors, Stanley R Riddell.
J Clin Invest, 2018 Jan 24; 128(4). PMID: 29360643    Free PMC article.
Highly Cited.
Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers.
Vivian W Y Lui, Matthew L Hedberg, +26 authors, Jennifer R Grandis.
Cancer Discov, 2013 Apr 27; 3(7). PMID: 23619167    Free PMC article.
Highly Cited.
Use of nonsteroidal anti-inflammatory drugs predicts improved patient survival for PIK3CA-altered head and neck cancer.
Matthew L Hedberg, Noah D Peyser, +20 authors, Jennifer R Grandis.
J Exp Med, 2019 Jan 27; 216(2). PMID: 30683736    Free PMC article.
Highly Cited.
Loss of TP63 Promotes the Metastasis of Head and Neck Squamous Cell Carcinoma by Activating MAPK and STAT3 Signaling.
Senthilnath Lakshmanachetty, Velmurugan Balaiya, Whitney A High, Maranke I Koster.
Mol Cancer Res, 2019 Mar 27; 17(6). PMID: 30910837    Free PMC article.
The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.
Ethan Cerami, Jianjiong Gao, +12 authors, Nikolaus Schultz.
Cancer Discov, 2012 May 17; 2(5). PMID: 22588877    Free PMC article.
Highly Cited.
Erk1/2 activation and modulation of STAT3 signaling in oral cancer.
Ioannis Gkouveris, Nikolaos Nikitakis, +2 authors, Alexandra Sklavounou.
Oncol Rep, 2014 Sep 02; 32(5). PMID: 25174327
Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.
Jianjiong Gao, Bülent Arman Aksoy, +10 authors, Nikolaus Schultz.
Sci Signal, 2013 Apr 04; 6(269). PMID: 23550210    Free PMC article.
Highly Cited.
Membranous expression of Her3 is associated with a decreased survival in head and neck squamous cell carcinoma.
Mikiko Takikita, Ran Xie, +5 authors, Stephen M Hewitt.
J Transl Med, 2011 Aug 02; 9. PMID: 21801427    Free PMC article.
Tumor mutational load predicts survival after immunotherapy across multiple cancer types.
Robert M Samstein, Chung-Han Lee, +54 authors, Luc G T Morris.
Nat Genet, 2019 Jan 16; 51(2). PMID: 30643254    Free PMC article.
Highly Cited.
Clinical implications of human papillomavirus in head and neck cancers.
Carole Fakhry, Maura L Gillison.
J Clin Oncol, 2006 Jun 10; 24(17). PMID: 16763272    Free PMC article.
Highly Cited. Review.
Next-generation characterization of the Cancer Cell Line Encyclopedia.
Mahmoud Ghandi, Franklin W Huang, +65 authors, William R Sellers.
Nature, 2019 May 10; 569(7757). PMID: 31068700    Free PMC article.
Highly Cited.
The prognostic role of tumor infiltrating T-lymphocytes in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis.
Emma J de Ruiter, Marc L Ooft, Lot A Devriese, Stefan M Willems.
Oncoimmunology, 2017 Nov 18; 6(11). PMID: 29147608    Free PMC article.
Highly Cited. Review.
Pentobarbital anesthesia and the response of tumor and normal tissue in the C3Hf/sed mouse to radiation.
H D Suit, R S Sedlacek, G Silver, D Dosoretz.
Radiat Res, 1985 Oct 01; 104(1). PMID: 4048394
IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade.
Mark Ayers, Jared Lunceford, +12 authors, Terrill K McClanahan.
J Clin Invest, 2017 Jun 27; 127(8). PMID: 28650338    Free PMC article.
Highly Cited.
Toward a Shared Vision for Cancer Genomic Data.
Robert L Grossman, Allison P Heath, +4 authors, Louis M Staudt.
N Engl J Med, 2016 Sep 23; 375(12). PMID: 27653561    Free PMC article.
Highly Cited.
Explore, Visualize, and Analyze Functional Cancer Proteomic Data Using the Cancer Proteome Atlas.
Jun Li, Rehan Akbani, +4 authors, Han Liang.
Cancer Res, 2017 Nov 03; 77(21). PMID: 29092939    Free PMC article.
TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells.
Taiwen Li, Jingyu Fan, +5 authors, X Shirley Liu.
Cancer Res, 2017 Nov 03; 77(21). PMID: 29092952    Free PMC article.
Highly Cited.
The mutational landscape of head and neck squamous cell carcinoma.
Nicolas Stransky, Ann Marie Egloff, +36 authors, Jennifer R Grandis.
Science, 2011 Jul 30; 333(6046). PMID: 21798893    Free PMC article.
Highly Cited.
Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors.
Diana Miao, Claire A Margolis, +28 authors, Eliezer M Van Allen.
Nat Genet, 2018 Aug 29; 50(9). PMID: 30150660    Free PMC article.
Highly Cited.
T-cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy.
Ignacio Melero, Ana Rouzaut, Greg T Motz, George Coukos.
Cancer Discov, 2014 May 06; 4(5). PMID: 24795012    Free PMC article.
Highly Cited.
Molecular and genetic properties of tumors associated with local immune cytolytic activity.
Michael S Rooney, Sachet A Shukla, +2 authors, Nir Hacohen.
Cell, 2015 Jan 17; 160(1-2). PMID: 25594174    Free PMC article.
Highly Cited.
Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy.
Y-P Chen, Y-Q Wang, +17 authors, J Ma.
Ann Oncol, 2018 Nov 09; 30(1). PMID: 30407504
Mutation load and an effector T-cell gene signature may distinguish immunologically distinct and clinically relevant lymphoma subsets.
Christopher R Bolen, Ronald McCord, +10 authors, Jeffrey M Venstrom.
Blood Adv, 2018 Jan 04; 1(22). PMID: 29296835    Free PMC article.
Quality of Life for Patients With Favorable-Risk HPV-Associated Oropharyngeal Cancer After De-intensified Chemoradiotherapy.
Kevin A Pearlstein, Kyle Wang, +13 authors, Bhishamjit S Chera.
Int J Radiat Oncol Biol Phys, 2018 Nov 06; 103(3). PMID: 30395903
Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial.
Maura L Gillison, Andy M Trotti, +24 authors, Quynh Thu Le.
Lancet, 2018 Nov 20; 393(10166). PMID: 30449625    Free PMC article.
Highly Cited.
Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.
Ahmet Zehir, Ryma Benayed, +97 authors, Michael F Berger.
Nat Med, 2017 May 10; 23(6). PMID: 28481359    Free PMC article.
Highly Cited.
Epidemiologic trends in head and neck cancer and aids in diagnosis.
Nadarajah Vigneswaran, Michelle D Williams.
Oral Maxillofac Surg Clin North Am, 2014 May 06; 26(2). PMID: 24794262    Free PMC article.
Highly Cited. Review.
The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC).
Ezra E W Cohen, R Bryan Bell, +16 authors, Robert L Ferris.
J Immunother Cancer, 2019 Jul 17; 7(1). PMID: 31307547    Free PMC article.
Highly Cited.
Utility of CD8 score by automated quantitative image analysis in head and neck squamous cell carcinoma.
Douglas J Hartman, Fahad Ahmad, +2 authors, Liron Pantanowitz.
Oral Oncol, 2018 Nov 10; 86. PMID: 30409313    Free PMC article.
Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial.
Hisham Mehanna, Max Robinson, +29 authors, De-ESCALaTE HPV Trial Group.
Lancet, 2018 Nov 20; 393(10166). PMID: 30449623    Free PMC article.
Highly Cited.
Comprehensive analyses of tumor immunity: implications for cancer immunotherapy.
Bo Li, Eric Severson, +10 authors, X Shirley Liu.
Genome Biol, 2016 Aug 24; 17(1). PMID: 27549193    Free PMC article.
Highly Cited.
TCPA: a resource for cancer functional proteomics data.
Jun Li, Yiling Lu, +11 authors, Han Liang.
Nat Methods, 2013 Sep 17; 10(11). PMID: 24037243    Free PMC article.
Highly Cited.
Somatic Mutations and Genetic Variants of NOTCH1 in Head and Neck Squamous Cell Carcinoma Occurrence and Development.
Yu-Fan Liu, Shang-Lun Chiang, +11 authors, Ying-Chin Ko.
Sci Rep, 2016 Apr 02; 6. PMID: 27035284    Free PMC article.
Comprehensive Exome Analysis of Immunocompetent Metastatic Head and Neck Cancer Models Reveals Patient Relevant Landscapes.
Hui Li, Hoi-Lam Ngan, +8 authors, Vivian Wai Yan Lui.
Cancers (Basel), 2020 Oct 16; 12(10). PMID: 33053752    Free PMC article.
BMPR2 expression level is correlated with low immune infiltration and predicts metastasis and poor survival in osteosarcoma.
Hongxin Cao, Shuang Quan, +2 authors, Guangjun Jiao.
Oncol Lett, 2021 Mar 30; 21(5). PMID: 33777214    Free PMC article.
Novel deep learning-based survival prediction for oral cancer by analyzing tumor-infiltrating lymphocyte profiles through CIBERSORT.
Yeongjoo Kim, Ji Wan Kang, +6 authors, Yun Hak Kim.
Oncoimmunology, 2021 Apr 16; 10(1). PMID: 33854823    Free PMC article.
Prognostic Gene Signature for Squamous Cell Carcinoma with a Higher Risk for Treatment Failure and Accelerated MEK-ERK Pathway Activity.
Bohai Feng, Kai Wang, +5 authors, Jochen Hess.
Cancers (Basel), 2021 Oct 24; 13(20). PMID: 34680330    Free PMC article.