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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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Mechanisms of Resistance to Target Therapies in Non-small Cell Lung Cancer

Francesco Facchinetti1, Claudia Proto2, Roberta Minari1

  • 1Medical Oncology Unit, University Hospital of Parma, Via Gramsci, 14, Parma, 43126, Italy.

Handbook of Experimental Pharmacology
|March 24, 2017
PubMed

Insights

Targeted therapies for non-small cell lung cancer (NSCLC) face resistance. Understanding diverse resistance mechanisms, like target alterations and pathway activation, is crucial for developing new treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Targeted therapies have transformed advanced non-small cell lung cancer (NSCLC) treatment, particularly for EGFR-mutated or ALK-rearranged lung adenocarcinoma.
  • Therapy resistance is inevitable, driven by emerging drug-insensitive cell populations.
  • Resistance mechanisms are broadly categorized into target alterations, alternative pathway activation, and phenotype transformation.

Purpose of the Study:

  • To review and synthesize current knowledge on resistance mechanisms to targeted therapies in oncogene-addicted NSCLC.
  • To discuss the implications of these mechanisms for developing novel therapeutic strategies.
  • To highlight the challenges posed by the heterogeneity and multiplicity of resistance mechanisms.

Main Methods:

  • Literature review of studies on targeted therapy resistance in NSCLC.
  • Classification of resistance mechanisms based on molecular and cellular changes.
  • Analysis of emerging therapeutic strategies and novel drug development.

Main Results:

  • Identified three main categories of resistance: target alterations (e.g., EGFR T790M, ALK mutations), alternative pathway activation (e.g., MET amplification, KRAS mutations), and phenotype transformation (e.g., small cell lung cancer, epithelial-mesenchymal transition).
  • Highlighted the development of next-generation inhibitors like osimertinib and new ALK-TKIs to overcome specific resistance mutations.
  • Emphasized the complexity arising from the potential co-occurrence of multiple resistance mechanisms and intratumoral heterogeneity.

Conclusions:

  • Understanding the diverse mechanisms of resistance to targeted therapies in NSCLC is essential for clinical progress.
  • Novel therapeutic strategies are being developed to combat resistance, including next-generation inhibitors.
  • Addressing the heterogeneity and complexity of resistance mechanisms remains a significant challenge in NSCLC treatment.
Keywords:
ALKEGFRNSCLCROS-1Resistance mechanismsT790M

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