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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Tolerance and Resistance to Targeted Therapy in NSCLC: Emerging Concepts and Strategies

Montse Sanchez-Cespedes1, William W Lockwood2, Kenichi Suda3

  • 1Cancer Genetics Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain; Histology Unit, Department of Cell Biology, Physiology, and Immunology, Cytology, Universitat Autonoma de Barcelona, Cerdanyola del Valles, Spain.

JTO Clinical and Research Reports
|March 20, 2026
PubMed

Insights

Targeted therapies for non-small cell lung cancer (NSCLC) have improved outcomes, but drug resistance remains a major hurdle. New strategies are emerging to overcome genetic and non-genetic resistance mechanisms in NSCLC treatment.

Area of Science:

  • Oncology
  • Genetics
  • Pharmacology

Background:

  • Epidermal growth factor receptor (EGFR) mutations heralded targeted therapy in non-small cell lung cancer (NSCLC).
  • Numerous targeted therapies for NSCLC, acting on nine different genes, have improved patient outcomes.
  • Acquired resistance and tumor tolerance limit the durability of these life-saving therapies.

Purpose of the Study:

  • To summarize current understanding of drug resistance mechanisms in NSCLC targeted therapy.
  • To discuss emerging concepts and novel strategies for overcoming resistance and improving treatment durability.
  • To present insights from the International Association for the Study of Lung Cancer Hot Topics Meeting.

Main Methods:

  • Review and synthesis of recent findings on drug resistance in NSCLC targeted therapy.
  • Discussion of genetic and non-genetic resistance mechanisms.
  • Exploration of novel therapeutic approaches presented at a major lung cancer conference.

Main Results:

  • Drug resistance in NSCLC is driven by complex genetic and non-genetic factors.
  • Mechanisms include drug-tolerant persister cells, tumor plasticity, heterogeneity, and microenvironmental influences.
  • New therapeutic strategies are being developed to combat these resistance pathways.

Conclusions:

  • Understanding resistance mechanisms is crucial for advancing NSCLC targeted therapy.
  • Combating drug tolerance and resistance requires a multi-faceted approach.
  • Novel strategies hold promise for improving long-term outcomes in NSCLC patients.
Keywords:
ALK fusionBasic scienceBiomarkersEGFR mutationNovel therapeuticsTranslational research

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