The EGFR family members sustain the neoplastic phenotype of ALK+ lung adenocarcinoma via EGR1

Abstract

In non-small cell lung cancer (NSCLC), receptor tyrosine kinases (RTKs) stand out among causal dominant oncogenes, and the ablation of RTK signaling has emerged as a novel tailored therapeutic strategy. Nonetheless, long-term RTK inhibition leads invariably to acquired resistance, tumor recurrence and metastatic dissemination. In ALK+ cell lines, inhibition of ALK signaling was associated with coactivation of several RTKs, whose pharmacological suppression reverted the partial resistance to ALK blockade. Remarkably, ERBB2 signaling synergized with ALK and contributed to the neoplastic phenotype. Moreover, the engagement of wild-type epidermal growth factor receptor or MET receptors could sustain cell viability through early growth response 1 (EGR1) and/or Erk1/2; Akt activation and EGR1 overexpression prevented cell death induced by combined ALK/RTK inhibition. Membrane expression of ERBB2 in a subset of primary naive ALK+ NSCLC could be relevant in the clinical arena. Our data demonstrate that the neoplastic phenotype of ALK-driven NSCLC relays ‘ab initio' on the concomitant activation of multiple RTK signals via autocrine/paracrine regulatory loops. These findings suggest that molecular and functional signatures are required in de novo lung cancer patients for the design of efficacious and multi-targeted ‘patient-specific' therapies.

Oncogenic ALK regulates EMT in non-small cell lung carcinoma through repression of the epithelial splicing regulatory protein 1

“…In keeping with the mRNA data, the protein expression levels of PRL-1 decreased and were dependent on ALK kinase activity (Figure 3C). Interestingly, one of the genes identified in the screening with the RT 2 Profiler PCR array was ERBB3 that was strongly up-regulated after ALK inhibition both as mRNA (Figure 2B) and protein (Supplementary Figure 1A), consistent with our previous findings [43]. …”

“…In contrast, in H2228 cells treatment with TAE-684 increased cell migration and invasion, suggesting the activation of compensatory pathways to sustain or even increase this phenotype (Supplementary Figure 5A-5B). We and others previously demonstrated that the EGFR family members can induce resistance to ALK TKIs by activating by-pass compensatory signaling pathways in ALK-rearranged NSCLC [43, 46, 47] and are associated to EMT in different tumors types [48, 49]. Since we observed an up-regulation of both mRNA and protein levels of ERBB3 in TAE-684-inhibited H2228 cells (Figure 2B and Supplementary Figure 1A), we hypothesized an involvement of ERBB receptors in TAE-684 induced increased migration in H2228 cells.…”

Efficacy of a Cancer Vaccine against ALK-Rearranged Lung Tumors

“…S5E). To further confirm that PD-L1 expression was driven by ALK activity, and to exclude that PD-L1 down-regulation was mediated by crizotinib inhibition of MET, ROS1, or other off-targets, we knocked down EML4-ALK by a doxycycline inducible shRNA system (16). Again, PD-L1 expression was down-regulated upon EML4-ALK knock-down (Supplementary Fig.…”

“…Next-generation ALK TKIs, such as ceritinib and alectinib, have been developed to overcome crizotinib resistance and can further extend survival in crizotinib-resistant patients (10–12). Resistance to ALK TKIs is mediated by point mutations of the ALK kinase domain, by ALK gene amplification, or by activation of other compensatory pathways, so-called bypass tracks, such as EGFR, c-KIT, c-MET, and IGF-R1 (8,13–16). Thus, additional therapies to be combined with ALK TKIs are needed to further prolong remission or clinical response in NSCLC patients with ALK rearrangements.…”

ALK-Dependent Control of Hypoxia-Inducible Factors Mediates Tumor Growth and Metastasis

“…In ALCL, ALK oncogenic signals are mediated by a series of key molecules and pathways, including STAT3, PI3K, RAS/MAPK/ERK, SHP2, p130CAS, PLCg, and Src (2,5). In NSCLC, conversely, downstream pathways are less extensively characterized (6).…”