Abstract PR05: ERK pathway activation is associated with acquired resistance to AZD9291, a third-generation irreversible inhibitor targeting EGFR sensitizing (EGFRm+) and resistance (T790M) mutations in NSCLC

摘要: First- and second-generation EGFR tyrosine kinase inhibitors (TKIs) are established first line therapies for patients with advanced NSCLC activating/sensitising mutations in EGFR. Unfortunately, ultimately develop disease progression acquisition of a second-site T790M mutation more than half cases. This has led to the development third generation TKIs such as AZD9291 which inhibit both EGFRm+ preclinical models, showing activity TKI-resistant tumors harbouring Phase I studies. Despite potential improvements brought by EGFR-TKIs, tumor cells will still remain highly adaptable, inevitability further resistance potentially limit effectiveness these drugs. As such, identification mechanisms agents is essential guide future therapeutic strategies identify novel:novel combinations. To interrogate AZD9291, we have generated panels cell populations resistant gefitinib (first TKI), EGFRm+/T790M afatinib (second TKI) WZ4002 or (third TKIs). Subsequently, characterized lines using phenotypic screen compare sensitivity small molecule canonical signaling pathways between parental populations. In addition used variety molecular profiling techniques determine DNA copy number status mRNA expression profile panel cancer associated genes within The effects on survival across range models pathway inhibitors, combination originating TKI, indicated that was frequently increased selumetinib (AZD6244; ARRY-142886) (MEK1/2 inhibitor), suggesting ERK commonly reactivated circumvent inhibition pathway. Further, analysis presence NRAS, including novel E63K mutation, NRAS KRAS 12/25 3/9 representing settings respectively. Analysis functional consequence observed RAS modifications confirmed their role driving addicted when inhibited. Collectively, data suggest activation, particular result acquired other TKI inhibitors. suggests combining could prevent delay resistance, therefore drive superior duration benefit compared alone. Citation Format: Cath Eberlein, Katie Al-Kadhimi, Sarah Ross, Henry Brown, Paul Fisher, Daniel Stetson, Zhongwu Lai, Kenneth Thress, Brian Dougherty, William Pao, Darren Cross. activation third-generation irreversible inhibitor targeting sensitizing (EGFRm+) (T790M) NSCLC. [abstract]. In: Proceedings AACR Precision Medicine Series: Drug Sensitivity Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Res 2015;21(4 Suppl): Abstract nr PR05.