Drug Vulnerabilities and Disease Prognosis Linked to the Stem Cell-Like Gene Expression Program Triggered by the RHO GTPase Activator VAV2 in Hyperplastic Keratinocytes and Head and Neck Cancer

SIMPLE SUMMARY: Head and neck squamous cell carcinoma are epithelial tumors with a very poor prognosis. They are also in high need of new targeted and immune-based therapeutics to limit tumor recurrence and improve long-term survival. The poor prognosis of patients with head and neck tumors is usually associated with histological features associated with poor differentiation and high proliferative activity found in their tumor biopsies. Therefore, it is of paramount importance to identify vulnerabilities associated with such pathobiological programs. In this work, the authors utilize a stem cell-like program linked to the deregulated activity of VAV2, a protein frequently overexpressed in this type of tumors, to identify new therapeutic targets that can discriminate tumors from healthy cells. The authors also show that this gene expression program can be used to stratify patients according to long-term prognosis. ABSTRACT: We have recently shown that VAV2, a guanosine nucleotide exchange factor that catalyzes the stimulation step of RHO GTPases, is involved in a stem cell-like (SCL) regenerative proliferation program that is important for the development and subsequent maintenance of the tumorigenesis of both cutaneous (cSCC) and head and neck squamous cell carcinomas (hnSCC). In line with this, we have observed that the levels of the VAV2 mRNA and VAV2-regulated gene signatures are associated with poor prognosis in the case of human papillomavirus-negative hnSCC patients. These results suggest that the SCL program elicited by VAV2 in those cells can harbor therapeutically actionable downstream targets. We have addressed this issue using a combination of both in silico and wet-lab approaches. Here, we show that the VAV2-regulated SCL program does harbor a number of cell cycle- and signaling-related kinases that are essential for the viability of undifferentiated keratinocytes and hnSCC patient-derived cells endowed with high levels of VAV2 activity. Our results also show that the VAV2-regulated SCL gene signature is associated with poor hnSCC patient prognosis. Collectively, these data underscore the critical role of this VAV2-regulated SCL program for the viability of both preneoplastic and fully transformed keratinocytes.