Del Re Marzia, Tiseo Marcello, Bordi Paola, D'Incecco Armida, Camerini Andrea, Petrini Iacopo, Lucchesi Maurizio, Inno Alessandro, Spada Daniele, Vasile Enrico, Citi Valentina, Malpeli Giorgio, Testa Enrica, Gori Stefania, Falcone Alfredo, Amoroso Domenico, Chella Antonio, Cappuzzo Federico, Ardizzoni Andrea, Scarpa Aldo, Danesi Romano
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Medical Oncology Unit, Azienda Ospedaliero-Universitaria, Parma, Italy.
Oncotarget. 2017 Feb 21;8(8):13611-13619. doi: 10.18632/oncotarget.6957.
KRAS oncogene mutations (MUTKRAS) drive resistance to EGFR inhibition by providing alternative signaling as demonstrated in colo-rectal cancer. In non-small cell lung cancer (NSCLC), the efficacy of treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) depends on activating EGFR mutations (MUTEGFR). However, inhibition of EGFR may select resistant cells displaying alternative signaling, i.e., KRAS, or restoration of EGFR activity due to additional MUTEGFR, i.e., the c.2369C > T (p.T790MEGFR).
The aim of this study was to investigate the appearance of MUTKRAS during EGFR-TKI treatment and their contribution to drug resistance.
This study used cell-free circulating tumor DNA (cftDNA) to evaluate the appearance of codon 12 MUTKRAS and p.T790MEGFR mutations in 33 advanced NSCLC patients progressing after an EGFR-TKI.
p.T790MEGFR was detected in 11 (33.3%) patients, MUTKRAS at codon 12 in 3 (9.1%) while both p.T790MEGFR and MUTKRAS codon 12 were found in 13 (39.4%) patients. Six patients (18.2%) were KRAS wild-type (WTKRAS) and negative for p.T790MEGFR. In 8 subjects paired tumor re-biopsy/plasma samples were available; the percent concordance of tissue/plasma was 62.5% for p.T790MEGFR and 37.5% for MUTKRAS. The analysis of time to progression (TTP) and overall survival (OS) in WTKRAS vs. MUTKRAS were not statistically different, even if there was a better survival with WTKRAS vs. MUTKRAS, i.e., TTP 14.4 vs. 11.4 months (p = 0.97) and OS 40.2 vs. 35.0 months (p = 0.56), respectively.
MUTKRAS could be an additional mechanism of escape from EGFR-TKI inhibition and cftDNA is a feasible approach to monitor the molecular development of drug resistance.
KRAS致癌基因突变（MUTKRAS）通过提供替代信号传导驱动对表皮生长因子受体（EGFR）抑制的耐药性，这在结直肠癌中已得到证实。在非小细胞肺癌（NSCLC）中，EGFR酪氨酸激酶抑制剂（EGFR-TKIs）的治疗效果取决于激活EGFR突变（MUTEGFR）。然而，抑制EGFR可能会选择显示替代信号传导的耐药细胞，即KRAS，或由于额外的MUTEGFR（即c.2369C>T（p.T790MEGFR））导致EGFR活性恢复。
本研究的目的是调查EGFR-TKI治疗期间MUTKRAS的出现情况及其对耐药性的影响。
本研究使用游离循环肿瘤DNA（cftDNA）评估33例在EGFR-TKI治疗后病情进展的晚期NSCLC患者中第12密码子MUTKRAS和p.T790MEGFR突变的出现情况。
在11例（33.3%）患者中检测到p.T790MEGFR，3例（9.1%）患者检测到第12密码子的MUTKRAS，13例（39.4%）患者同时检测到p.T790MEGFR和第12密码子的MUTKRAS。6例患者（18.2%）为KRAS野生型（WTKRAS）且p.T790MEGFR为阴性。在8例患者中可获得配对的肿瘤再次活检/血浆样本；p.T790MEGFR的组织/血浆一致性百分比为62.5%，MUTKRAS为37.5%。WTKRAS与MUTKRAS的进展时间（TTP）和总生存期（OS）分析无统计学差异, 尽管WTKRAS的生存期优于MUTKRAS，即TTP分别为14.4个月对11.4个月（p = 0.97），OS分别为40.2个月对35.0个月（p = 0.56）。
MUTKRAS可能是逃避EGFR-TKI抑制的另一种机制, 且cftDNA是监测耐药性分子发展的可行方法。
