Umelo Ijeoma Adaku, De Wever Olivier, Kronenberger Peter, Van Deun Jan, Noor Alfiah, Singh Kshitiz, Teugels Erik, Chen Gang, Bracke Marc, De Grève Jacques
Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, Universitair Ziekenhuis Brussel, Brussels, Belgium.
Laboratory of Experimental Cancer Research and Department of Radiotherapy, Universitair Ziekenhuis Gent, Brussels, Belgium.
Oncotarget. 2015 Aug 21;6(24):20132-44. doi: 10.18632/oncotarget.3853.
KRAS is a frequently mutated oncogene in lung cancer and among the most refractory to EGFR targeted therapy. Recently, preclinical evidence in pancreatic cancer has demonstrated that mutant KRAS can be regulated by EGFR. However, the distinct correlation between the EGFR/HER family members and mutant KRAS has not been investigated. Here, we show that non-small cell lung cancer cell lines harboring differing isoforms of mutant KRAS, can be broadly divided into EGFR/HER dependent and EGFR/HER independent groups. Combined therapeutic targeting of EGFR, HER2 and HER3 in isoforms regulated by extracellular growth signals promotes in vitro and in vivo efficacy. We also provide evidence that depletion of EGFR via RNA interference specifically abolishes the EGFR/KRAS interaction in the dependent subset. Taken together, these findings suggest that upstream inhibition of the EGFR/HER receptors may be effective in treating a subset of KRAS mutant lung cancers.
KRAS是肺癌中一种常见的突变致癌基因，也是对EGFR靶向治疗最具耐药性的基因之一。最近，胰腺癌的临床前证据表明，突变型KRAS可受EGFR调控。然而，EGFR/HER家族成员与突变型KRAS之间的独特相关性尚未得到研究。在此，我们表明，携带不同异构体的突变型KRAS的非小细胞肺癌细胞系可大致分为EGFR/HER依赖性和EGFR/HER非依赖性两组。在由细胞外生长信号调节的异构体中，联合靶向EGFR、HER2和HER3进行治疗可提高体外和体内疗效。我们还提供证据表明，通过RNA干扰使EGFR缺失可特异性消除依赖性亚组中的EGFR/KRAS相互作用。综上所述，这些发现表明，EGFR/HER受体的上游抑制可能对治疗一部分KRAS突变型肺癌有效。
