EPHA2 feedback activation limits the response to PDE? inhibition in KRAS-dependent cancer cells.

ABSTRACT: KRAS is one of the most important proto-oncogenes. Its mutations occur in almost all tumor types, and KRAS mutant cancer is still lack of effective therapy. Prenyl-binding protein phosphodiesterase-? (PDE?) is required for the plasma membrane association and subsequent activation of KRAS oncogenic signaling. Recently, targeting PDE? has provided new promise for KRAS mutant tumors. However, the therapeutic potential of PDE? inhibition remains obscure. In this study, we explored how PDE? inhibition was responded in KRAS mutant cancer cells, and identified KRAS mutant subset responsive to PDE? inhibition. We first performed siRNA screen of KRAS growth dependency of a small panel of human cancer lines, and identified a subset of KRAS mutant cancer cells that were highly dependent on KRAS signaling. Among these cells, only a fraction of KRAS-dependent cells responded to PDE? depletion, though KRAS plasma membrane association was effectively impaired. We revealed that the persistent RAF/MEK/ERK signaling seemed responsible for the lack of response to PDE? depletion. A kinase array further identified that the feedback activation of EPH receptor A2 (EPHA2) accounted for the compensatory activation of RAF/MEK/ERK signaling in these cells. Simultaneous inhibition of EPHA2 and PDE? led to the growth inhibition of KRAS mutant cancer cells. Together, this study gains a better understanding of PDE?-targeted therapeutic strategy and suggests the combined inhibition of EPHA2 and PDE? as a potential therapy for KRAS mutant cancer.

SUBMITTER: Chen YH 

PROVIDER: S-EPMC7471410 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature