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Abstract
The expanding spectrum of both established and candidate oncogenic driver mutations
identified in non-small-cell lung cancer (NSCLC), coupled with the increasing number
of clinically available signal transduction pathway inhibitors targeting these driver
mutations, offers a tremendous opportunity to enhance patient outcomes. Despite these
molecular advances, advanced-stage NSCLC remains largely incurable due to therapeutic
resistance. In this Review, we discuss alterations in the targeted oncogene ('on-target'
resistance) and in other downstream and parallel pathways ('off-target' resistance)
leading to resistance to targeted therapies in NSCLC, and we provide an overview of
the current understanding of the bidirectional interactions with the tumour microenvironment
that promote therapeutic resistance. We highlight common mechanistic themes underpinning
resistance to targeted therapies that are shared by NSCLC subtypes, including those
with oncogenic alterations in epidermal growth factor receptor (EGFR), anaplastic
lymphoma kinase (ALK), ROS1 proto-oncogene receptor tyrosine kinase (ROS1), serine/threonine-protein
kinase b-raf (BRAF) and other less established oncoproteins. Finally, we discuss how
understanding these themes can inform therapeutic strategies, including combination
therapy approaches, and overcome the challenge of tumour heterogeneity.