Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by a mutant or amplified KRAS oncogene, is a significant challenge in the treatment of colorectal cancer (CRC). However, the mechanism of KRAS-mediated therapeutic resistance is not well understood. In this study, we demonstrate that clinically used anti-EGFR antibodies, including cetuximab and panitumumab, induce killing of sensitive CRC cells through p73-dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein PUMA. PUMA induction and p73 activation are abrogated in CRC cells with acquired resistance to anti-EGFR antibodies due to KRAS alterations. Inhibition of aurora kinases preferentially kills mutant KRAS CRC cells and overcomes KRAS-mediated resistance to anti-EGFR antibodies in vitro and in vivo by restoring PUMA induction. Our results suggest that PUMA plays a critical role in meditating the sensitivity of CRC cells to anti-EGFR antibodies, and that restoration of PUMA-mediated apoptosis is a promising approach to improve the efficacy of EGFR-targeted therapy.

中文翻译：

---

恢复 PUMA 诱导可克服结直肠癌中 KRAS 介导的抗 EGFR 抗体耐药性。


对抗 EGFR 抗体治疗的内在和获得性耐药通常由突变或扩增的 KRAS 癌基因介导，是结直肠癌 (CRC) 治疗中的重大挑战。然而，KRAS 介导的治疗耐药的机制尚不清楚。在这项研究中，我们证明临床使用的抗 EGFR 抗体（包括西妥昔单抗和帕尼单抗）通过 p73 依赖性促凋亡 Bcl-2 家族蛋白 PUMA 的转录激活来诱导杀死敏感的 CRC 细胞。由于 KRAS 改变，对抗 EGFR 抗体产生耐药性的 CRC 细胞中 PUMA 诱导和 p73 激活被取消。极光激酶的抑制优先杀死突变的 KRAS CRC 细胞，并通过恢复 PUMA 诱导来克服体外和体内 KRAS 介导的抗 EGFR 抗体耐药性。我们的研究结果表明，PUMA 在调节 CRC 细胞对抗 EGFR 抗体的敏感性中发挥着关键作用，并且恢复 PUMA 介导的细胞凋亡是提高 EGFR 靶向治疗功效的有前途的方法。