Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer

Abstract

Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non‐small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide‐3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR‐TKI‐resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single‐agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal‐epithelial transition factor amplification, induction of epithelial‐to‐mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long‐term treatment with the combination therapy induced the conversion from EMT to mesenchymal‐to‐epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR‐TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR‐TKIs.

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

“…Investigating the mechanism revealed that inhibiting PDE4D restored tamoxifen sensitivity through induction of the unfolded protein response and subsequent activation of p38 and JNK. In lung cancer, blocking the downstream effectors MEK or PI3K is ineffective in overcoming resistance to EGFR inhibitors [142]. However, combined MEK and PI3K blockade successfully interfered with features of malignant transformation caused by drug-resistant EGFR mutants.…”

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer

“…6 Another acquired resistance mechanism to EGFR-TKIs is up-regulation of the RAS/ RAF/MEK/ERK signaling pathway, key to cell survival and proliferation 7,8 ; this can occur downstream of various other signaling pathways. 9 Combination targeted therapy may overcome genomic heterogeneity of drug resistance. However, the risk of overlapping toxicities and resulting dose adjustments can impede effective combinations.…”

Serum microRNA-365 suppresses non-small-cell lung cancer metastasis and invasion in patients with bone metastasis of lung cancer

“… 19 The PI3K/Akt pathway is regarded as the primary pathway of cancer cell survival. 20 Inhibition of the EGFR/PI3K/Akt signaling pathway has been shown to suppress the survival and migration of NSCLC cell lines. 20 We confirmed that downregulation of miRNA-365 suppressed protein expression of NKX2-1 and induced expression of EGFR, PI3K, and p-Akt protein in vitro.…”