Mitogen-activated protein kinase (MAPK) pathway aberrations in head and neck squamous cell carcinoma

Abstract

 Head and neck squamous cell carcinoma (HNSCC) is an aggressive and hard-to-treat cancer with high rates of treatment failure. Thus, more effective therapies need to be developed. Recent findings in HNSCC suggest the potential druggabiilty of MAPK(ERK) pathway in HNSCC, and its clinical promises as a drug-responsive signaling node in HNSCC. To better understand the druggable potential of MAPK(ERK) pathway in HNSCC, I investigated the MAPK(ERK)-associated signaling network in HNSCC cell models. Interestingly, I found that MAPK1 activating mutations could upregulate p53 protein expressions in both TP53 wild-type (WT) or mutated HNSCC cells. Conversely, pharmacological inhibition of MAPK (ERK) by a specific ERK inhibitor, GDC-0994 caused a marked p53 protein downregulation in HNSCC cells bearing p53 WT or p53-mutant proteins. Wild-type and mutant p53 proteins differ functionally in HNSCC oncogenesis and treatment-responsiveness. Thus, our study revealed that this potentially drug-responsive MAPK(ERK) pathway appeared to be intrinsically linked to p53 protein expression in HNSCC. Therefore, careful consideration of the p53 mutational status is needed when drugging the MAPK(ERK) signaling in HNSCC. It is because wild-type and mutant p53 proteins differ functionally in HNSCC oncogenesis and treatment-responsiveness. As MAPK pathway aberrations are commonly detected in HNSCC patient tumors, I examined the prognostic significance of MAPK pathway aberrations (both genomic or proteomic aberrations) using the largest US HNSCC cohort. In summary, I discovered that ARAF overexpression was a strong independent prognostic factor for HNSCC overall survival (OS). Similar findings were observed with overexpression of another MAPK pathway protein, phospho-BRAF (S445). Strikingly, mutations of major kinases of the MAPK pathway, and loss of negative regulators of this pathway were also associated with better clinical outcomes in patients. Thus, for the first time, an “activated MAPK(ERK) mitogenic pathway” was found to tie to favourable clinical outcomes in HNSCC patients. Supportive data from subsequent in vitro experiments showed that MAPK-mutated cell lines were more sensitive to chemotherapy, and were likely to exhibit a less aggressive phenotype upon chemotherapy treatment. These in vitro findings may explain in part our favourable clinical observations of MAPK(ERK) pathway “activated” HNSCC patients. Thus, MAPK pathway activation (at genomic or proteomic levels) may serve as a potential biomarker for HNSCC prognosis.