PO-211 KRAS driven lung adenocarcinoma depends on ERBB signalling

Abstract

IntroductionSeveral clinical trials using first generation EGFR Tyrosine Kinase Inhibitors (TKIs, erlotinib and gefitinib) in patients suffering of lung adenocarcinoma (AC) harbouring activating mutations in the KRAS gene have shown disappointing results. Therefore, it has become a doctrine that KRAS driven lung AC do not respond to TKIs and targeting EGFR (and other ERBB family members) is not considered a therapeutic option to treat patients suffering of KRAS mutated lung AC. Challenging these observations, we demonstrate that KRAS driven lung AC responds to the pan-ERBB inhibitor afatinib.Material and methodsPrimary human tumour samples, human/murine cancer cell lines, xenografts, PDXs and GEMMs. Genetic and pharmacological manipulations.Results and discussionsAnalysis of human and murine tumour samples showed activation of the ERBB receptors and expression of their ligands in KRAS driven lung AC. Furthermore, human KRAS mutated advance tumours (stage II and more advance AC) were enriched in the ERBB gene expression signatures compared to stage I tumours. Experimentally, we found that genetic deletion of EGFR in a GEMM of KRAS driven lung AC or in human xenografted A549 cells significantly reduced tumorigenesis, irrespectively of the p53 status. Tumours lacking EGFR showed less cell proliferation and reduce activation of KRAS downstream effectors. Pharmacological inhibition of EGFR using erlotinib or gefitinib failed to inhibit tumorigenesis in KRAS driven lung AC experimental models. On the contrary, afatinib (an irreversible pan-ERBB inhibitor) was effective in human/murine cell lines, xenograft, PDXs and GEMMs models. Detailed analysis of this observation revealed that genetic deletion or pharmacology inhibition (erlotinib/gefitinib) of the EGFR in KRAS driven lung AC results in a tumor-escape mechanism relying in the activation of other ERBB receptor family members (namely ERBB2 and ERBB3) that can be blocked with the pan-ERBB inhibitor afatinib.ConclusionIn conclusion, our data shows that KRAS driven lung AC is depending on ERBB signalling. Importantly, we have unravelled a tumor-escape mechanism depending on the (re)activation of non-EGFR ERBB receptors that explains the poor results in previous clinical trials using erlotinib and gefitinib in patients suffering KRAS mutated lung AC. In agreement with this, pan-ERBB inhibition using afatinib effectively abrogates KRAS driven lung AC. Thus, afatinib or other pan-ERBB inhibitors should be a therapeutic option to treat patients suffering of KRAS driven lung AC.