148IN - Can we Do Better with Our Current Therapies for Nsclc? the Spanish Lung Cancer Group Approach

Abstract

ABSTRACT Aim: In the SLCG large-scale screening, 16.6% of EGFR mutations were found, median PFS and OS for pts receiving erlotinib was 14 mos and 27 mos, respectively. The HR for the duration of PFS was 1.68 for the presence of L858R mutation in paired serum DNA (P = 0.02) (NEJM 2009; 361:958-67). Mutant EGFR NSCLC selectively activates STAT3 signaling which promotes cell survival and single EGFR inhibition can even enhance STAT3 activation. Growing evidence shows that targeting STAT3 or upstream or downstream components could improve the outcome. Hence, the resistance mechanisms should be revised, T790M is detected in 60% before therapy (reported by SLCG) and MET signaling can cause inter-receptor crosstalk with AXL, EPHA2, JAK1 and CDCP1. BIM mRNA expression is an independent predictive marker of response to erlotinib (reported by SLCG). High BIM can predict response and early adaptive resistance via IL6-STAT3-Bcl2. In those patients with low BIM, STAT3 can be activated through over-expression of AXL and EPHA2. Crosstalk between TGFb and NOTCH signaling can also be involved. Methods: Transcripts involving STAT3 signaling were examined from 80 EGFR mutant NSCLC pts, including BIM, STAT3 and SHP2. Also MET, AXL, Mer, EphA2 and Gas6 were analyzed. Together with TGFb and NOTCH constituents: ADAM17, NUMB, HES1, DUSP1, RBJ, LncRNA-ATB, SLUG, GLI and PKCi. Repurposing drugs, in combination with gefitinib, erlotinib and afatinib, were examined in cell cultures and in subcutaneous and orthotopic xenograft mice models. Results: Data will be presented on the correlation of BIM and SHP2 with regard to the mechanism of activation of STAT3 and the influence in response, PFS and OS in the 80 erlotinib-treated EGFR mutant NSCLC pts, and the influence of the above mentioned signaling constituents. Early data shows synergism of gefitinib with AXL inhibitor in the PC9-R cells. Also, activity of niclosamide and paclitaxel. Conclusions: Based on the results, the SLCG-GFCP will carry out a trial with erlotinib in combination with the most active repurposing drugs found, customized by BIM expression. Disclosure: All authors have declared no conflicts of interest.