Inactivation of p21-Activated Kinase 2 (Pak2) Inhibits the Development of Nf2 -Deficient Malignant Mesothelioma

Malignant mesotheliomas (MM) show frequent somatic loss of the tumor suppressor gene. The product, Merlin, is implicated in several tumor-related pathways, including p21-activated kinase (PAK) signaling. Merlin is both a phosphorylation target for PAK and a negative regulator of this oncogenic kinase. Merlin loss results in PAK activation, and PAK inhibitors hold promise for the treatment of -deficient tumors. To test this possibility in an genetic system, mice were crossed to mice with conditional knockout of , a highly expressed group I Pak member. Cohorts of these animals were injected in either the thoracic or peritoneal cavities with adeno-Cre virus to delete floxed alleles in the mesothelial lining. Loss of resulted in a markedly decreased incidence and delayed onset and progression of pleural and peritoneal MMs in mice, as documented by Kaplan-Meier survival curves and bioluminescent imaging. RNA-seq revealed that MMs from mice showed downregulated expression of genes involved in several oncogenic pathways (Wnt, Akt) when compared to MMs from mice retaining Pak2. Kinome profiling showed that, as compared to MM cells, MM cells had multiple kinase changes indicative of an epithelial to mesenchymal transition. Collectively, these findings suggest that MMs adapt by reprogramming their kinome and gene signature profiles to bypass the need for PAK activity via the activation of other compensatory oncogenic kinase pathways. The identification of such secondary pathways offers opportunities for rational combination therapies to circumvent resistance to anti-PAK drugs.