Mechanisms of NSCLC EGFR-mutant Cell Lines Developing Treatment-Adaptive Resistance In vitro

Abstract

NSCLC ranks at the top of lung carcinoma cases worldwide, with three generations of EGFR-TKIs used in clinics where resistance derives ultimately. Molecular mechanisms have been underscored for their contribution to resistance. More recent studies reported the first-line therapy Osimertinib gives rise to the acquired T790M and C797S mutations, addressing the necessity of inhibitor usage. Therapeutic windows occur by the lung-specific hydroxylase mimicry and pVHL agonists development for HIF-1α high-accuracy degradation, considering the correlation between HIF-1α and other signaling pathways. This paper analyzed the in vitro research on the role of MAPK and PI3K-Akt pathway, NF-κB pathway, and hypoxia-regulated HIF-1α signaling in generating EGFR-TKI resistance and obtained the results of further validation in the inhibitors used for the pathways blockage. The pathways involved trigger the hallmarks of cancer and stimulate inflammation under stressed conditions. Meanwhile, inhibitors failed in their function due to misleading signal engagement, technical weakness, and off-target effects. With new target emergence, it drives a potential of constant disruption in resistance-associated pathways. However, the target feasibility and practical drug development pipeline have not been revealed and require future studies.