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Precision drugging of the MAPK pathway in head and neck cancer.

ABSTRACT: The mitogen-activating protein kinase (MAPK) pathway is central for cell proliferation, differentiation, and senescence. In human, germline defects of the pathway contribute to developmental and congenital head and neck disorders. Nearly 1/5 of head and neck squamous cell carcinoma (HNSCC) harbors MAPK pathway mutations, which are largely activating mutations. Yet, previous approaches targeting the MAPK pathway in HNSCC were futile. Most recent clinical evidences reveal remarkable, or even exceptional pharmacologic vulnerabilities of MAPK1-mutated, HRAS-mutated, KRAS-germline altered, as well as BRAF-mutated HNSCC patients with various targeted therapies, uncovering diverse opportunities for precision drugging this pathway at multiple "genetically condemned" nodes. Further, recent patient tumor omics unveil novel effects of MAPK aberrations on direct induction of CD8⁺ T cell recruitment into the HNSCC microenvironment, providing evidences for future investigation of precision immunotherapy for this large subset of patients. MAPK pathway-mutated HNSCC should warrant precision therapy assessments in vigorous manners.

SUBMITTER: Ngan HL

PROVIDER: S-EPMC8927572 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Precision drugging of the MAPK pathway in head and neck cancer.

Ngan Hoi-Lam HL Law Chun-Ho CH Choi Yannie Chung Yan YCY Chan Jenny Yu-Sum JY Lui Vivian Wai Yan VWY

NPJ genomic medicine 20220316 1

The mitogen-activating protein kinase (MAPK) pathway is central for cell proliferation, differentiation, and senescence. In human, germline defects of the pathway contribute to developmental and congenital head and neck disorders. Nearly 1/5 of head and neck squamous cell carcinoma (HNSCC) harbors MAPK pathway mutations, which are largely activating mutations. Yet, previous approaches targeting the MAPK pathway in HNSCC were futile. Most recent clinical evidences reveal remarkable, or even excep ...[more]

PMID: 35296678

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Project description:BackgroundLocoregionally advanced, recurrent, and metastatic squamous cell carcinomas of the head and neck (SCCHN) remain difficult to treat disease entities, in which systemic treatment often forms an integral part of their management. Immunotherapy is based on functional restoration of the host immune system, helping to counteract various tumour evasion strategies. Broadly, immunotherapeutic approaches encompass tumour-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating agents. Until 2015, the epidermal growth factor receptor inhibitor cetuximab, a tumour-specific antibody, represented the only Food and Drug Administration (FDA)-approved targeted therapy for SCCHN. Subsequently, in 2016, the results from two prospective trials employing the immune-modulating antibodies nivolumab and pembrolizumab heralded a new era of anticancer treatment.DiscussionNivolumab and pembrolizumab are monoclonal antibodies against programmed cell death protein-1 (PD-1), an 'immune checkpoint' receptor. Found on the surface of T-cells, PD-1 negatively regulates their activation and can thus be exploited during carcinogenesis. The second-line phase III trial CheckMate-141 randomly assigned 361 patients with recurrent and/or metastatic SCCHN in a 2:1 ratio to receive either single-agent nivolumab (3 mg/kg intravenously every 2 weeks) or standard monotherapy (methotrexate, docetaxel, or cetuximab). Nivolumab improved the objective response rate (13% versus 6%) and median overall survival (OS; 7.5 versus 5.1 months, p = 0.01) without increasing toxicity. Exploratory biomarker analyses indicated that patients treated with nivolumab had longer OS than those given standard therapy, regardless of tumour PD-1 ligand (PD-L1) expression or p16 status. In the non-randomised, multicohort phase Ib study KEYNOTE-012, treatment with pembrolizumab achieved comparable results. Importantly, most of the responding patients had a long-lasting response.ConclusionBased on recent results, nivolumab and pembrolizumab have been approved by the FDA as new standard-of-care options for the second-line treatment of recurrent and/or metastatic SCCHN. Generally well tolerated, these novel drugs demonstrated modest response rates, with tumour regressions usually being durable, even in platinum-resistant/refractory cases. The next step will be to extend the observed benefit to first-line treatment, currently dominated by the EXTREME regimen (platinum/5-fluorouracil/cetuximab), and to the locoregionally advanced setting, where concurrent chemoradiation with cisplatin is standard. Regimens combining immunotherapy with other modalities will probably further improve outcomes.

Dataset Information

Precision drugging of the MAPK pathway in head and neck cancer.

Publications

Precision drugging of the MAPK pathway in head and neck cancer.

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