Resistance to dual blockade of the kinases PI3K and mTOR in KRAS-mutant colorectal cancer models results in combined sensitivity to inhibition of the receptor tyrosine kinase EGFR
Resistance to dual blockade of the kinases PI3K and mTOR in KRAS-mutant colorectal cancer models results in combined sensitivity to inhibition of the receptor tyrosine kinase EGFR
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DOI：
10.1126/scisignal.2005516
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发表时间：
2014-11-11
影响因子：
7.3
通讯作者：
Martin, Eric S.
中科院分区：
文献类型：
--
作者：
Belmont, Peter J.;Jiang, Ping;Martin, Eric S.
靶向阻断异常激活的信号通路是一种有吸引力的治疗实体瘤的策略，但耐药是常见的。KRAS是人类癌症中经常发生突变的基因，但仍然是一个具有挑战性的临床靶点。针对KRAS信号介质的抑制剂，即PI3K（磷脂酰肌醇3-激酶）和mTOR（雷帕霉素的机制靶点），作为单一药物治疗KRAS突变型结直肠癌（CRC）的临床疗效有限。我们研究了kras突变CRC中PI3K/mTOR抑制的潜在旁路机制。使用对PI3K/mTOR双小分子抑制剂PF-04691502产生抗性的基因工程小鼠模型细胞，我们通过化学文库筛选确定，ERBB[表皮生长因子受体（EGFR）]家族抑制剂恢复了对PF-04691502的敏感性。虽然单独使用EGFR抑制剂在减少KRASmutant肿瘤方面的效果有限，但我们发现，gf -04691502通过激活FOXO3a (forkhead box O3a)（一种被PI3K - AKT通路抑制的转录因子），诱导了EGFR、ERBB2和ERBB3的丰度、磷酸化和活性。PF-04691502也诱导了干细胞样基因表达特征。经PF-04691502处理的小鼠kras突变患者来源的异种移植物具有相似的基因表达特征，并表现出增加的EGFR激活，表明这种药物诱导的耐药机制可能发生在患者身上。联合dacomitinib（一种泛erbb抑制剂）治疗可恢复培养耐药细胞对PF-04691502的敏感性，并诱导耐药同种异体移植小鼠肿瘤消退。我们的研究结果表明，联合使用PI3K/mTOR和EGFR抑制剂可能改善kras突变型结直肠癌患者的治疗结果。
Targeted blockade of aberrantly activated signaling pathways is an attractive therapeutic strategy for solid tumors, but drug resistance is common. KRAS is a frequently mutated gene in human cancer but remains a challenging clinical target. Inhibitors against KRAS signaling mediators, namely, PI3K (phosphatidylinositol 3-kinase) and mTOR (mechanistic target of rapamycin), have limited clinical efficacy as single agents in KRAS-mutant colorectal cancer (CRC). We investigated potential bypass mechanisms to PI3K/mTOR inhibition in KRAS-mutant CRC. Using genetically engineered mouse model cells that had acquired resistance to the dual PI3K/mTOR small-molecule inhibitor PF-04691502, we determined with chemical library screens that inhibitors of the ERBB [epidermal growth factor receptor (EGFR)] family restored the sensitivity to PF-04691502. Although EGFR inhibitors alone have limited efficacy in reducing KRASmutant tumors, we found that PF-04691502 induced the abundance, phosphorylation, and activity of EGFR, ERBB2, and ERBB3 through activation of FOXO3a (forkhead box O 3a), a transcription factor inhibited by the PI3K to AKT pathway. PF-04691502 also induced a stem cell-like gene expression signature. KRAS-mutant patient-derived xenografts from mice treated with PF-04691502 had a similar gene expression signature and exhibited increased EGFR activation, suggesting that this drug-induced resistance mechanism may occur in patients. Combination therapy with dacomitinib (a pan-ERBB inhibitor) restored sensitivity to PF-04691502 in drug-resistant cells in culture and induced tumor regression in drug-resistant allografts in mice. Our findings suggest that combining PI3K/mTOR and EGFR inhibitors may improve therapeutic outcome in patients with KRAS-mutant CRC.