PDF(Pubmed)
Abstract：
Aberrant activation of RAS/MAPK signaling is common in cancer, and efforts to inhibit pathway components have yielded drugs with promising clinical activities. Unfortunately, treatment-provoked adaptive resistance mechanisms inevitably develop, limiting their therapeutic potential. As a central node essential for receptor tyrosine kinase-mediated RAS activation, SHP2 has emerged as an attractive cancer target. Consequently, many SHP2 allosteric inhibitors are now in clinical testing. Here we discovered a previously unrecognized off-target effect associated with SHP2 allosteric inhibitors. We found that these inhibitors accumulate in the lysosome and block autophagic flux in an SHP2-independent manner. We showed that off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their antitumor activity. We also demonstrated that SHP2 allosteric inhibitors harboring this off-target activity not only suppress oncogenic RAS signaling but also overcome drug resistance such as MAPK rebound and protective autophagy in response to RAS/MAPK pathway blockage. Finally, we exemplified a therapeutic framework that harnesses both the on- and off-target activities of SHP2 allosteric inhibitors for improved treatment of mutant RAS-driven and drug-resistant malignancies such as pancreatic and colorectal cancers.
摘要：
RAS-MAPK信号的异常激活在癌症中很常见，以及抑制途径成分的努力已经产生了具有有希望的临床活性的药物。不幸的是,治疗引发的适应性抗性机制不可避免地发展起来，限制了他们的治疗潜力。作为受体酪氨酸激酶介导的RAS激活所必需的中枢节点，SHP2已成为有吸引力的癌症靶标。因此,许多SHP2变构抑制剂现在正在临床试验中.在这里，我们发现了与SHP2变构抑制剂相关的先前未识别的脱靶效应。我们发现这些抑制剂在溶酶体中积累并以不依赖SHP2的方式阻断自噬通量。我们表明，SHP2变构抑制剂的脱靶自噬抑制有助于其抗肿瘤活性。我们还证明，具有这种脱靶活性的SHP2变构抑制剂不仅抑制致癌RAS信号传导，而且还克服了耐药性，如响应RAS-MAPK通路阻断的MAPK反弹和保护性自噬。最后,我们举例说明了一个治疗框架,该框架利用SHP2变构抑制剂的靶向和脱靶活性,改善了突变型RAS驱动的和耐药的恶性肿瘤如胰腺癌和结直肠癌的治疗.简介：SHP2变构抑制剂引发脱靶自噬阻断，可用于改善RAS驱动和耐药癌症的治疗。
