Ludwig Institute for Cancer Research, Austin Health, Level 6 Harold Stokes Building, 145-163 Studley Road, Heidelberg, Victoria 3084, Australia.
Curr Cancer Drug Targets. 2010 Dec;10(8):824-33. doi: 10.2174/156800910793357961.
Mutations in K-Ras are observed in approximately 40% of colon tumours. This has significant implications for predicting likelihood of response to the antibody-based EGFR inhibitors, cetuximab and panitumumab, with K-Ras mutant patients now clearly shown to be inherently resistant to these agents. Alternative treatment strategies for K-Ras mutant patients are therefore urgently needed. Farnesyltransferase inhibitors, developed to inhibit K-Ras, have to-date been largely unsuccessful. However, a number of agents which target signaling components in the MAPK and PI3K pathways downstream of mutant K-Ras are currently being evaluated in clinical trials and will be discussed. A further clinical concern is that K-Ras wild type patients who initially respond to EGFR inhibitors eventually develop acquired resistance to these agents and experience tumour progression. Studies from the use of related agents in other disease settings as well as pre-clinical studies provide important insights into mechanisms by which this may occur. While no evidence presently exists for somatic mutations as a basis for acquired resistance to EGFR inhibitors in colon cancer, several studies implicate upregulation and signaling via other Her family members, c-Met, IGFR and Src. Upregulation of the pro-angiogenic factor, VEGF, is also a possible mechanism of acquired resistance. This review discusses drugs currently in clinical trials that may potentially achieve more efficient and prolonged targeting of the EGFR pathway by overcoming these mechanisms of resistance.
K-Ras 突变约见于 40%的结肠肿瘤。这对预测基于抗体的 EGFR 抑制剂（西妥昔单抗和帕尼单抗）的反应可能性具有重要意义，K-Ras 突变患者显然对这些药物具有内在抗性。因此，迫切需要为 K-Ras 突变患者寻找替代治疗策略。开发用于抑制 K-Ras 的法尼基转移酶抑制剂迄今为止基本没有成功。然而，目前有许多针对 MAPK 和 PI3K 信号通路下游突变型 K-Ras 信号成分的药物正在临床试验中进行评估，并将进行讨论。另一个临床关注的问题是，最初对 EGFR 抑制剂有反应的 K-Ras 野生型患者最终会对这些药物产生获得性耐药并经历肿瘤进展。来自其他疾病环境中使用相关药物的研究以及临床前研究为可能发生这种情况的机制提供了重要的见解。虽然目前没有证据表明体细胞突变是结肠癌对 EGFR 抑制剂获得性耐药的基础，但有几项研究表明，其他 Her 家族成员、c-Met、IGFR 和 Src 的上调和信号转导与此有关。促血管生成因子 VEGF 的上调也是获得性耐药的一种可能机制。这篇综述讨论了目前正在临床试验中的药物，这些药物可能通过克服这些耐药机制，更有效地靶向 EGFR 通路并延长其作用时间。
