Tumor progression locus 2 (Tpl2) is a member of the
mitogen-activated protein kinase kinase kinase (MAP3K) family of
serine/threonine kinases. Deletion of the Tpl2 gene is associated with a significantly higher number of
papillomas and cutaneous
squamous cell carcinomas (cSCCs). Overexpression of
hepatocyte growth factor (HGF) and its receptor MET is abundant in cSCC and can lead to increased proliferation, migration, invasion or resistance to
epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitors. The aim of this study was to address whether the increased
tumor burden in Tpl2 -/- mice is due to aberrant HGF/MET signaling. C57Bl/6 wild type (WT) and Tpl2 -/- mice were subjected to a two-stage chemical
carcinogenesis protocol for one year. At the time of promotion half of the mice received 44 mg/kg
capmatinib (INC 280), a pharmacological inihibitor of MET, in their diet. Tpl2-/- mice had signficantly higher
tumor incidence and overall
tumor burden compared to WT mice. Further,
carcinogen-intiated Tpl2 -/- mice could bypass the need for promotion, as 89% of Tpl2 -/- mice given only DMBA developed
papillomas. v-rasHa -transduced keratinocytes and SCCs from Tpl2 -/- mice revealed an upregulation in HGF and p-MET signaling compared to WT animals. Long-term
capmatinib treatment had no adverse effects in mice and
capmatinib-fed Tpl2 -/- mice had a 60% reduction in overall
tumor burden. Further, no
tumors from Tpl2 -/- mice fed
capmatinib underwent malignant conversion. In summary targeting MET may be a potential new strategy to combat cutaneous
squamous cell carcinomas that result from dysregulation in MAPK signaling.