New Therapeutic Opportunities for the Treatment of Squamous Cell Carcinomas: A Focus on Novel Driver Kinases

Abstract

Squamous cell carcinomas of the lung, head and neck, esophagus, and cervix account for more than two million cases of cancer per year worldwide with very few targetable therapies available and minimal clinical improvement in the past three decades. Although these carcinomas are differentiated anatomically, their genetic landscape shares numerous common genetic alterations. Amplification of the third chromosome's distal portion (3q) is a distinguishing genetic alteration in most of these carcinomas and leads to copy-number gain and amplification of numerous oncogenic proteins. This area of the chromosome harbors known oncogenes involved in squamous cell fate decisions and differentiation, including TP63, SOX2, ECT2, and PIK3CA. Furthermore, novel targetable oncogenic kinases within this amplicon include PRKCI, PAK2, MAP3K13, and TNIK. TCGA analysis of these genes identified amplification in more than 20% of clinical squamous cell carcinoma samples, correlating with a significant decrease in overall patient survival. Alteration of these genes frequently co-occurs and is dependent on 3q-chromosome amplification. The dependency of cancer cells on these amplified kinases provides a route toward personalized medicine in squamous cell carcinoma patients through development of small-molecules targeting these kinases.

Keywords: 3q amplicon; EGFR; MAPK; PI3K; PKC; cell signaling; kinases; oncogenes; receptor tyrosine kinases; squamous carcinomas.

Figure 1

Worldwide incidence of the major types of human cancers. Red bars indicate cancers that have a squamous cell carcinoma (SCC) subtype. Data acquired from GLOBOCAN 2018.

Figure 2

Amplification (red)/deletion (blue) frequency of the 3q amplicon kinase genes PIK3CA, PRKCI, MAP3K13, TNIK, and PAK2 in a The Cancer Genome Atlas (TCGA) pan-cancer analysis using cBioPortal. A minimum cutoff of 85 clinical samples was used per cancer type.

Figure 3

Survival statistics and amplification of 3q amplicon genes.

Figure 4

Alteration and mutation frequency of multiple genes within cervix (CvSCC), esophagus (ESCC), lung (LSCC), and head and neck (HNSCC) TCGA data sets using cBioPortal. Genes include the most altered gene, TP53; the HPV biomarker, CDKN2A; the 3q amplicon genes; and current genes being targeted in clinical trials. A total of 1317 patients were analyzed for gene alteration/mutation, of which 957 were analyzed for 3q status.