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A CRAF/glutathione-S-transferase P1 Complex Sustains Autocrine Growth Of Cancers WithKRASandBRAFmutations

Yoshiro Niitsu, Yasushi Sato, Kunihiro Takanashi, Tsuyoshi Hayashi, Naoko Kubo-Birukawa, Fumiko Shimizu, Naoki Fujitani, Rai Shimoyama, Takehiro Kukitsu, Wataru Kurata, Yasuyuki Tashiro, Irving Listowsky

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The Ras/RAF/MEK/ERK pathway is an essential signaling cascade for various refractory cancers, such as those with mutantKRAS(mKRAS) andBRAF(mBRAF). 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 mKRASand mBRAFcancer 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 mKRASand mBRAFcells in vitro and suppressed tumorigenesis of the xenografted mKRAStumor in vivo. GSTP1 knockout mice showed significantly impaired carcinogenesis of mKRAScolon cancer. Consequently, hindering the autocrine loop by targeting CRAF/GSTP1 interactions should provide innovative therapeutic modalities for these cancers.