MAPK1 Genomic Alterations as Predictor of Treatment Response and Driver for Tumor Growth in Head and Neck Cancer

Abstract:

Genomic characterization of exceptional clinical responders is an emerging and promising approach that has successfully accelerated the development of personalized therapy and the identification of (genetic) biomarkers for response in many cancer types. Using whole-exome sequencing, we have identified a tumor-specific MAPK1(E322K) mutation in a head and neck cancer (HNC) patient with extraordinary complete response to erlotinib (a clinically safe EGFR tyrosine kinase inhibitor; TKI), revealing a potential mechanism of mutati0n—driven sensitivity to EGFR TKI in HNC. Multi-cancer genomic analysis revealed this mutation as a hotspot mutation detected mainly in HNC, cervical cancer, and several Asian-prevalent cancers. Additional MAPK] mutations nearby this hotspot site are also found in HNC tumors. Findings in engineered stable HNC cells expressing this hotspot mutation, and a HNC cell line harboring endogenous MAPKI(E322K) mutation (originally derived from an Asian HNC patient) reveals its potent activity in driving high levels of MAPK activation and HNC cell growth, defining MAPK1(E322K) as an activating driver mutation in HNC. It was also noted that MAPK] gene amplification (also reported in HNC) is also a gotential driver for HNC growth. Strikingly, further signaling analysis revealed the ability of this hotspot mutation in driving robust increases in EGFR phosphorylation in HNC models, first demonstrating a novel mechanism of EGFR hygeractivation caused by MAPK] mutation in HNC. These clinical and preclinical findings led

us to hmothesize that MAPK] genomic aberrations are direct drivers [or HNC carcinogenesis,

and activating MAPK] mutationtsg can induce a state EGFR hygeractivation via undefined mechanism s in HNC cells thus sensiti in them to EGFR inhibition b erlotinib. Here, We

propose to: 1) compare the MAPK] genomic profiles (both mutation and gene copy number alterations) in Asian and US HNC patient tumors to define their clinical relevance in 2 major HNC populations; 2) determine the biological contributions of all HNC-associated MAPK] mutations and amplification to HNC growth, invasion and tumor-formation in vitro and in vivo; and 3) elucidate the mechanism(s) of erlotinib-sensitivity (in relation to p-EGFR upregulation) conferred by MAPK1(E322K), and possibly other HNC-associated MAPK] mutations in HNC systems. The study not only defines the role of MAPK] genomic aberrations in HNC carcinogenesis, but also defines a novel molecular mechanism of heightened erlotinib sensitivity in HNC driven by MAPK] mutation, providing a genetic basis for personalized theragv in HNC that can impact patient/therapy selection (analogous to EGFR activating mutations in lung cancer), and potentially applicable to other MAPK] —mutated/EGFR—expressing cancers.