Guibert N, Ilie M, Long E, Hofman V, Bouhlel L, Brest P, Mograbi B, Marquette C H, Didier A, Mazieres J, Hofman P
Laboratoire de Pathologie Clinique et Experimentale, Hopital Pasteur, CHU de Nice, 30 avenue de la Voie Romaine, F-06002 Nice Cedex 1, France.
Curr Mol Med. 2015;15(5):418-32. doi: 10.2174/1566524015666150505161412.
KRAS mutations are detected in over one third of lung adenocarcinomas, most frequently in Caucasian and smoker patients. The impact of KRAS mutations on lung adenocarcinoma prognosis is currently subject to debate, as is their impact on the response to chemotherapy and EGFR tyrosine kinase inhibitors. The different methods for KRAS status assessment, based on histological and cytological samples or biological fluids, offer varying sensitivities. Since no treatments are available in clinical routine for KRAS-mutated lung cancer patients, one of the current major challenges in thoracic oncology is developing new dedicated strategic therapies. Different molecules can be developed that act on a post-transcriptional KRAS protein level, blocking its cytoplasmic membrane recruitment. The efficacy of these molecules' targeting of the different signaling pathways activated by the KRAS mutation (such as the MEK and BRAF pathways) is related to the particular KRAS mutation subtype. New therapeutic strategies are currently focused on certain genes linked with KRAS inducing a synthetic lethal interaction. The purpose of this work is to provide an overview of i) the recent epidemiological and molecular findings concerning KRASmutated lung adenocarcinoma, ii) the prognostic impact of KRAS mutations, in particular during response to treatment, iii) the available methods for detecting this mutation, and iv) the current molecules under development for new therapeutic strategies and the clinical trials targeting this genomic alteration.
在超过三分之一的肺腺癌中检测到KRAS突变，在白种人和吸烟患者中最为常见。KRAS突变对肺腺癌预后的影响目前存在争议，其对化疗和表皮生长因子受体（EGFR）酪氨酸激酶抑制剂反应的影响也存在争议。基于组织学和细胞学样本或生物体液的KRAS状态评估的不同方法具有不同的敏感性。由于临床常规中没有针对KRAS突变肺癌患者的治疗方法，因此胸部肿瘤学当前的主要挑战之一是开发新的专门战略疗法。可以开发不同的分子，这些分子作用于转录后KRAS蛋白水平，阻止其向细胞质膜募集。这些分子针对由KRAS突变激活的不同信号通路（如MEK和BRAF通路）的疗效与特定的KRAS突变亚型有关。目前新的治疗策略集中在与KRAS相关的某些基因上，这些基因会诱导合成致死相互作用。这项工作的目的是概述：i）关于KRAS突变肺腺癌的最新流行病学和分子研究结果；ii）KRAS突变的预后影响，特别是在治疗反应期间；iii）检测这种突变的可用方法；iv）目前正在开发的用于新治疗策略的分子以及针对这种基因组改变的临床试验。
