A CRAF/glutathione-S-transferase P1 complex sustains autocrine growth of cancers with <i>KRAS</i> and <i>BRAF</i> mutations.

Abstract

The Ras/RAF/MEK/ERK pathway is an essential signaling cascade for various refractory cancers, such as those with mutant <i>KRAS</i> (m<i>KRAS</i>) and <i>BRAF</i> (m<i>BRAF</i>). However, there are unsolved ambiguities underlying mechanisms for this growth signaling thereby creating therapeutic complications. This study shows that a vital component of the pathway CRAF is directly impacted by an end product of the cascade, glutathione transferases (GST) P1 (GSTP1), driving a previously unrecognized autocrine cycle that sustains proliferation of m<i>KRAS</i> and m<i>BRAF</i> cancer cells, independent of oncogenic stimuli. The CRAF interaction with GSTP1 occurs at its N-terminal regulatory domain, CR1 motif, resulting in its stabilization, enhanced dimerization, and augmented catalytic activity. Consistent with the autocrine cycle scheme, silencing GSTP1 brought about significant suppression of proliferation of m<i>KRAS</i> and m<i>BRAF</i> cells in vitro and suppressed tumorigenesis of the xenografted m<i>KRAS</i> tumor in vivo. GSTP1 knockout mice showed significantly impaired carcinogenesis of m<i>KRAS</i> colon cancer. Consequently, hindering the autocrine loop by targeting CRAF/GSTP1 interactions should provide innovative therapeutic modalities for these cancers.