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

Ras / RAF / MEK / ERK途径是各种难治性癌症（例如具有突变KRAS（m KRAS）和BRAF（m BRAF）的那些）的必不可少的信号级联。但是，这种生长信号转导的机制尚有未解决的歧义，从而产生治疗并发症。这项研究表明，CRAF通路的重要组成部分直接受到级联终产物谷胱甘肽转移酶（GST）P1（GSTP1）的影响，从而驱动了以前无法识别的自分泌周期，维持了m KRAS和m BRAF的增殖。癌细胞，独立于致癌刺激。CRAF与GSTP1的相互作用发生在其N末端调节域CR1基序上，从而使其稳定，增强了二聚化并增强了催化活性。与自分泌循环方案一致，沉默GSTP1可以显着抑制体外m KRAS和m BRAF细胞的增殖，并在体内抑制异种移植的m KRAS肿瘤的发生。GSTP1基因敲除小鼠显示出m KRAS结肠癌的致癌作用显着受损。因此，通过靶向CRAF / GSTP1相互作用来阻碍自分泌循环应为这些癌症提供创新的治疗方法。