Precision drugging of the MAPK pathway in head and neck cancer

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.

Automated summary

The MAPK pathway plays a central role in cell proliferation, differentiation and senescence. Defects in this pathway can contribute to developmental and congenital head and neck disorders in humans, and a significant portion of head and neck squamous cell carcinoma cases have MAPK pathway mutations. Recent clinical evidence suggests that targeted therapies can be effective in treating these patients, and there is also potential for precision immunotherapy based on the effects of MAPK aberrations on immune cell recruitment.