Mechanisms of osimertinib resistance and emerging treatment options.

Lung Cancer : Journal of the International Association for the Study of Lung Cancer
Sabine SchmidNatasha B Leighl

Abstract

Osimertinib is an irreversible EGFR-tyrosine kinase inhibitor initially approved for treatment of EGFR-positive patients exhibiting a T790 M resistance mutation in the second line setting and now emerging as the new standard of care for all EGFR positive patients as first-line treatment. Despite its efficacy, resistance to osimertinib inevitably develops and mechanisms of resistance can be grouped broadly in two categories: on-target EGFR-dependent and off-target EGFR-independent mechanisms. EGFR-dependent resistance typically is associated with additional EGFR-mutations disrupting the osimertinib binding through changes in the binding site by allosteric/ conformational transitions; EGFR-independent mechanisms are related mostly to alternate pathway activation or aberrant downstream signalling but also to lineage plasticity leading to small cell transformation. MET amplification is the most frequent off-target mechanisms of resistance to osimertinib treatment and recently published early trials show promising results for combination of MET-inhibitors with osimertinib upon development of resistance. This review will summarize mechanisms of resistance overall and in different treatment settings and will focus on potential new tre...Continue Reading

Citations

Apr 5, 2021·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Kentaro TanakaIsamu Okamoto
Apr 24, 2021·Respiratory Medicine and Research·K El Husseini, M Wislez
Aug 20, 2021·Therapeutic Advances in Medical Oncology·Nikolaus MagiosPetros Christopoulos

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