Department of Chemistry and Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 261 Roger Adams Lab Box 36-5, 600 S. Mathews Avenue, Urbana, IL 61801, USA.
Department of Chemistry and Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 261 Roger Adams Lab Box 36-5, 600 S. Mathews Avenue, Urbana, IL 61801, USA.
Cell Chem Biol. 2018 Aug 16;25(8):996-1005.e4. doi: 10.1016/j.chembiol.2018.05.008. Epub 2018 Jun 14.
The discovery of mutant or fusion kinases that drive oncogenesis, and the subsequent approval of specific inhibitors for these enzymes, has been instrumental in the management of some cancers. However, acquired resistance remains a significant problem in the clinic, limiting the long-term effectiveness of most of these drugs. Here we demonstrate a general strategy to overcome this resistance through drug-induced MEK cleavage (via direct procaspase-3 activation) combined with targeted kinase inhibition. This combination effect is shown to be general across diverse tumor histologies (melanoma, lung cancer, and leukemia) and driver mutations (mutant BRAF or EGFR, fusion kinases EML4-ALK and BCR-ABL). Caspase-3-mediated degradation of MEK kinases results in sustained pathway inhibition and substantially delayed or eliminated resistance in cancer cells in a manner far superior to combinations with MEK inhibitors. These data suggest the generality of drug-mediated MEK kinase cleavage as a therapeutic strategy to prevent resistance to targeted anticancer therapies.
突变或融合激酶的发现驱动了肿瘤的发生，随后针对这些酶的特定抑制剂获得批准，这对一些癌症的治疗起到了重要作用。然而，获得性耐药仍然是临床上的一个重大问题，限制了大多数这些药物的长期疗效。在这里，我们展示了一种通过药物诱导的 MEK 切割（通过直接的 procaspase-3 激活）与靶向激酶抑制相结合来克服这种耐药性的通用策略。这种组合效应在不同的肿瘤组织学（黑色素瘤、肺癌和白血病）和驱动突变（突变 BRAF 或 EGFR、融合激酶 EML4-ALK 和 BCR-ABL）中均得到了证明。半胱天冬酶-3 介导的 MEK 激酶降解导致持续的通路抑制，并以远优于与 MEK 抑制剂联合使用的方式，显著延迟或消除了癌细胞的耐药性。这些数据表明，药物介导的 MEK 激酶切割作为一种预防针对癌症的靶向治疗的耐药性的治疗策略具有普遍性。
