Targeting mutant EGFR in non-small cell lung cancer in the context of cell adaptation and resistance.

Activating mutations in the catalytic kinase domain of the epidermal growth factor receptor (EGFR) are crucial drivers of non-small cell lung cancer (NSCLC). Our understanding of the structural changes induced by such mutations has evolved alongside the rational design of targeted tyrosine kinase inhibitors (TKIs), leading to improved anti-tumor responses through appropriate patient stratification. However, challenges remain, including a growing number of therapy adaptation mechanisms and acquired resistance, which are further complicated by the intricate signaling networks of EGFR. Here, we review the rational development and targeting of EGFR-TKIs in the context of TKI-induced cellular death, adaptation, resistance, and eventual clinical failure, to provide a birds-eye view of this highly multidisciplinary field. We end by proposing new approaches based on our developing understanding of the quaternary structure of EGFR, which leverage in situ oligomer architectures to develop therapies that modulate EGFR oligomer-specific interactions and exploit weaknesses in its downstream signaling network to overcome resistance.