RHO guanine nucleotide exchange factors (GEF), a group of enzymes associated with the catalytic activation of RHO GTPases, have been traditionally associated with protumorigenic functions in a variety of tumor contexts. However, we have found that the VAV3 GEF plays unexpected tumor suppressor roles in the case of non-small cell lung cancer (NSCLC). In this abstract, we will provide information about this role and the potential signaling mechanism involved.

We utilized two mouse NSCLC models: (i) urethane-induced NSCL using wild-type and Vav3–/– mice; and (ii) KrasG12D/+ and KrasG12D/+;Vav3–/– mice . We also have used murine and human NSCLC cell lines in which endogenous VAV3 was knockdown by shRNA-mediated approaches. As control, we used similar models in which VAV2, another member of the RHO GEF family, was eliminated using analogous techniques. These models were characterized using signaling and cell biology analyses; rescue experiments with VAV3 mutants and downstream signaling elements; RNA-seq; and LC MS/MS-based proteomics.

We found that animals lacking Vav3 exhibited increased tumor burden and aggressiveness. In line with this, the elimination of endogenous VAV3 in lung cancer cells lead to increased cell growth and cell cycle progression. This is specific for VAV3, because the elimination of VAV2 induces opposite effects in urethane- and K-RASG12D-driven lung tumorigenesis. Signaling and rescue analyses performed in control and VAV3 knockdown NSCLC cells reveal the implication of specific RHO and PKN kinase family members in this suppressor role. The distal elements that mediate the final suppression effect are now under characterization.

These results demonstrate that VAV3 acts as a tumor suppressor in NSCLC, possibly via the modulation of a RHO–PKN-dependent pathway that impacts on cell cycle progression.