TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer

Abstract

The epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor erlotinib has been proven to be highly effective in the treatment of nonsmall cell lung cancer (NSCLC) harboring oncogenic EGFR mutations. The majority of patients, however, will eventually develop resistance and succumb to the disease. Recent studies have identified secondary mutations in the EGFR (EGFR T790M) and amplification of the N-Methyl-N′-nitro-N-nitroso-guanidine (MNNG) HOS transforming gene (MET) oncogene as two principal mechanisms of acquired resistance. Although they can account for approximately 50% of acquired resistance cases together, in the remaining 50%, the mechanism remains unknown. In NSCLC-derived cell lines and early-stage tumors before erlotinib treatment, we have uncovered the existence of a subpopulation of cells that are intrinsically resistant to erlotinib and display features suggestive of epithelial-to-mesenchymal transition (EMT). We showed that activation of TGF-β–mediated signaling was sufficient to induce these phenotypes. In particular, we determined that an increased TGF-β–dependent IL-6 secretion unleashed previously addicted lung tumor cells from their EGFR dependency. Because IL-6 and TGF-β are prominently produced during inflammatory response, we used a mouse model system to determine whether inflammation might impair erlotinib sensitivity. Indeed, induction of inflammation not only stimulated IL-6 secretion but was sufficient to decrease the tumor response to erlotinib. Our data, thus, argue that both tumor cell-autonomous mechanisms and/or activation of the tumor microenvironment could contribute to primary and acquired erlotinib resistance, and as such, treatments based on EGFR inhibition may not be sufficient for the effective treatment of lung-cancer patients harboring mutant EGFR.

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

“…This is in line with previous work by others showing that EGFR TKI-resistant EGFR-mutant cells with an EMT phenotype were uniformly not dependent on Met kinase. [5][6][7] Collectively, these findings suggest that Met signaling does not have a key role in inducing or maintaining EMT of EGFR-mutant lung cancer cells.…”

“…Although the GR cells analyzed here were selected from cell lines in vitro, studies show that some EGFR-mutant lung cancers with acquired TKI resistance display an EMT phenotype in the clinic. [5][6][7][8] Like EGFR-mutant lung cancer, chronic myeloid leukemia, which has the Bcr-Abl fusion gene, 32 and gastrointestinal stromal tumors, which harbors an activating mutation in the c-kit gene, 33 are addicted to constitutively activated tyrosine kinases. Intriguingly, these In this study, we have also uncovered that GR cells have a higher degree of basal autophagy than their parental cells, which endows them with the potential to evade apoptosis and proliferate even under hypoxic conditions in vitro.…”

“…We also observed a marked increase in CD44 expression in GR cells as compared with their parental cells ( Figure 1b). As parental HCC827 and HCC4006 cell lines contain a minor subpopulation of cells that express CD44 (o1%), 5 it is likely that gefitinib treatment selected for these pre-existing GR cells from the parental cell culture.…”

“…4 EGFR-mutated tumors can also acquire resistance to EGFR TKIs through epithelial-tomesenchymal transition (EMT). [5][6][7][8] Furthermore, the AXL receptor tyrosine kinase has been shown to have a key role in EMT-induced drug resistance; 9 however, it remains unclear whether AXL activation invariably occurs in EGFR-mutant carcinoma cells showing an EMT phenotype.…”

Afatinib, a lung cancer inhibitor of ErbB family

“…Thus, tailored drugs are able to eradicate cancer cells harboring the "targetable marker" but often produce resistance mechanisms causing only partial and temporary responses in patients. To this end, it would be of note to cite unambiguous studies, analyzing in details those targeted therapies and the crucial contribution of environmental factors to treatment responses and answering the question on how cancer is able to counteract those therapies (Yao et al 2010;Sun et al 2012;Weizman et al 2013), thus definitively suggest the existence of a further layer in the complexity of cancer-drug resistance. Therefore, we might question whether these tailored drugs are the best choice for cancer therapy or whether the clinical use of molecular-targeted therapy treatment should be taking into the account the possibility of adjunctive therapies, based on the unique genetic-driven biology in each patient.…”