Abstract
Clinical PI3K inhibition has been somewhat disappointing, due to both inadequate patient stratification and compensatory cell signalling through bypass mechanisms. As such, investigation of PI3K-MEK co-targeted inhibition has been recommended. With high mortality rates and a clear need for new therapeutic intervention strategies, non-small cell lung cancer (NSCLC) is an important setting to investigate the effectiveness of this approach.Here, 174 NSCLC tumours were screened for 150 mutations by Fluidigm technology, with 15 patients being profiled for phosphoprotein expression. The effects of GDC-0941 (a pan PI3K inhibitor), GDC-0980 (a dual PI3K/mTOR inhibitor) and GDC-0973 (a MEK inhibitor) alone and in combination were assessed in 3 NSCLC cell lines.PIK3CA was mutated in 5.17% of NSCLC patients. GDC-0941 and GDC-0980 treatment induced anti-proliferative and pro-apoptotic responses across all NSCLC cell lines, while GDC-0973 treatment induced only anti-proliferative responses. GDC-0980 and GDC-0973 combined treatment led to significant increases in apoptosis and synergistic reductions in proliferation across the panel of cell lines.This study found that the PI3K/MEK co-targeted inhibition strategy is synergistic in all 3 molecular subtypes of NSCLC investigated. Consequently, we would advocate clinical trials for NSCLC patients combining GDC-0980 and GDC-0973, each of which are separately under clinical investigation currently.
Highlights
Lung cancer incidence and treatment strategiesIn 2013, lung cancer was the leading cause of cancer related death in men, accounting for 1.3 million male deaths worldwide, along with 535,000 female deaths [1]
Both pmTOR and pS6RP were significantly more highly expressed in tumour tissue than matched normal tissue samples (Figure 1). 4 of these 15 patients harboured a mutation in PIK3CA, which did not correlate with phosphoprotein expression
PIK3CA mutation status is known to be associated with PI3K pathway activation, which in turn is known to be involved in carcinogenesis
Summary
Lung cancer incidence and treatment strategiesIn 2013, lung cancer was the leading cause of cancer related death in men, accounting for 1.3 million male deaths worldwide, along with 535,000 female deaths [1]. Several key “driver” genes are mutated in NSCLC including, epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), KRAS, human epidermal growth factor receptor 2 (HER2), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), MET, phosphatidylinositol 3-kinase catalytic α (PIK3CA), AKT and mitogen-activated protein kinase kinase 1 (MAP2K1). These aberrant genes are obvious targets for inhibition. PI3K-AKT-mTOR signalling is known to play a role in carcinogenesis and tumour progression, and mutations have been reported in PIK3CA in a range of human cancers These PIK3CA mutations most www.impactjournals.com/oncotarget frequently affect residues Glu542 and Glu545 encoding the catalytic domain, and His1047 encoding the kinase domain [2]. It has been hypothesized that a portion of PIK3CAmutant lung cancers could be dependent on PIK3CA as a driver oncogene, whereas in other cases, the PIK3CA mutation may modulate the effect of another oncogenic process [7]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.