Resistance to EGFR-TKI Can Be Mediated through Multiple Signaling Pathways Converging upon Cap-Dependent Translation in EGFR-Wild Type NSCLC

Abstract

INTRODUCTION For the majority of patients with non-small cell lung cancer, response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) is suboptimal. In models of acquired resistance to EGFR-TKI, activation of Akt phosphorylation is frequently observed. Since Akt activation results in downstream initiation of cap-dependent protein translation, we hypothesized that a strategy of targeting cap-dependent translation in combination with erlotinib might enhance therapy. METHODS NSCLC cells that are wild-type for Egfr were assayed for sensitivity to erlotinib. Serum-starved NSCLC cells were assayed for EGFR signaling and downstream pathway activation by immunoblot after stimulation with EGF. EGFR signaling and signaling mediators of cap-dependent translation were assayed by immunoblot under serum replete conditions 24 hours after treatment with erlotinib. Finally, combination treatment with erlotinib and 2 different cap-dependent translation inhibitors were done to assess the effect on cell viability. RESULTS EGFR signaling is coupled to activation of cap-dependent translation in EGFR wild-type cells. Erlotinib inhibits EGFR phosphorylation in EGFR-TKI resistant cells, however, results in activation of downstream signaling molecules including Akt and ERK1/2 resulting in maintenance of eIF4F activation. eIF4F cap-complex formation is maintained in erlotinib resistant cells, but not in erlotinib sensitive cells. Finally, using an antisense oligonucleotide against eIF4E and a small-molecule inhibitor to disrupt eIF4F formation, we show that cap-dependent translation inhibition can enhance sensitivity to erlotinib. Conclusions The results of these studies support further clinical development of translation inhibitors for treatment of NSCLC in combination with erlotinib.

NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer

“…Indeed, induced (Figure S4L) and constitutive (Figure 4H) shedding of EGF as determined by the expression of an EGF-alkaline phosphatase (AP) construct followed by measurement of AP activity in the supernatant revealed decreased EGF shedding in KPn organoids and in Nrf2 -deficient tumor cells (Figure S4M). Consistent with reports showing that EGFR signaling is coupled to activation of cap-dependent translation in EGFR wild type cells (Patel et al, 2013), EGF supplementation was able to restore defective Akt and Erk activation in KPn organoids (Figure S4N). Addition of NAC alone also partially corrected these signaling defects (Figure S4N) and restored EGF release (Figure S4O).…”

Pim-1 kinase is a target of miR-486-5p and eukaryotic translation initiation factor 4E, and plays a critical role in lung cancer

“…Here we found that siRNA-mediated Pim-1 knockdown increased the sensitivity of NSCLC cells to cisplatin. Furthermore, EGFR signaling was recently suggested to couple to activation of cap-dependent translation in EGFR wild-type NSCLC cells [ 33 ]. Resistance to EGFR-TKI can be mediated through multiple signaling pathways converging upon cap-dependent translation in EGFR-wild type NSCLC.…”

“…Resistance to EGFR-TKI can be mediated through multiple signaling pathways converging upon cap-dependent translation in EGFR-wild type NSCLC. Using an antisense oligonucleotide against eIF4E to disrupt cap-dependent translation can enhance sensitivity to erlotinib [ 33 ]. Interestingly, our present study showed that Pim-1 was involved in the efficacy of EGFR targeted therapies in NSCLC cells with wild-type EGFR.…”

The regulation of Neuropilin 1 expression by miR‐338‐3p promotes non‐small cell lung cancer via changes in EGFR signaling

“…However, some patients with lung cancer with wild-type EGFR benefit from EGFR-TKI therapy, 9,10 possibly because resistance to EGFR-TKIs can be mediated through multiple signalling pathways that converge upon cap-dependent translation in NSCLC cells expressing wild-type EGFR. 11,12 Interestingly, our previous study showed that CD73 affected the efficacy of EGFR-targeted therapies in NSCLC cells with wild-type EGFR. 13 Thus, based on the literature, we hypothesized that NRP1 plays a role in the EGF signalling pathway and that knockdown of NRP1 expression might sensitize NSCLC cells to therapeutic agents.…”