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Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
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Acquired resistance mechanisms to osimertinib: The constant battle

Ziad Zalaquett1, Maria Catherine Rita Hachem1, Yara Kassis1

  • 1Department of Hematology-Oncology, Hôtel-Dieu de France University Hospital, Saint Joseph University of Beirut, Beirut, Lebanon.

Cancer Treatment Reviews
|April 15, 2023
PubMed

Insights

Osimertinib is a targeted therapy for EGFR-mutated lung cancer. This review details mechanisms of osimertinib resistance, aiming to find new treatments to improve patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Lung cancer is a leading cause of cancer mortality globally.
  • Targeted therapies, including epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), have improved prognosis for patients with EGFR-mutated non-small-cell lung cancer (NSCLC).
  • Osimertinib, a third-generation EGFR-TKI, is effective in first-line treatment for stage IV EGFR-mutated NSCLC, including cases with the T790M resistance mutation.

Purpose of the Study:

  • To review the molecular mechanisms of resistance to osimertinib in EGFR-mutated NSCLC.
  • To identify potential therapeutic strategies to overcome osimertinib resistance.
  • To improve treatment outcomes for patients with advanced NSCLC.

Main Methods:

  • Comprehensive literature review of studies on osimertinib resistance mechanisms.
  • Classification of resistance mechanisms into EGFR-dependent and EGFR-independent categories.
  • Analysis of emerging resistance pathways and their clinical implications.

Main Results:

  • Resistance to osimertinib is a significant clinical challenge.
  • EGFR-dependent resistance is primarily mediated by the C797S mutation.
  • EGFR-independent resistance involves bypass signaling pathways, oncogenic fusions, and phenotypic alterations.

Conclusions:

  • Understanding diverse resistance mechanisms is crucial for developing next-generation therapies.
  • Combination strategies targeting both primary and acquired resistance are needed.
  • Further research into overcoming osimertinib resistance will enhance therapeutic efficacy and patient survival in NSCLC.
Keywords:
EGFR inhibitorsNon-small cell lung cancerOsimertinibResistance mechanismsTargeted therapy

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