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Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
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Understanding and targeting resistance mechanisms in NSCLC

Julia Rotow1,2, Trever G Bivona1,2,3

  • 1Department of Medicine, Division of Hematology and Oncology, University of California San Francisco, 505 Parnassus Avenue, Box 1270, San Francisco, California 94143, USA.

Nature Reviews. Cancer
|October 26, 2017
PubMed

Insights

Targeted therapies for non-small-cell lung cancer (NSCLC) show promise but face resistance. Understanding on-target and off-target resistance mechanisms, including tumor microenvironment interactions, is key to improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Non-small-cell lung cancer (NSCLC) has a growing list of identified oncogenic driver mutations.
  • Targeted therapies inhibiting these mutations offer improved patient outcomes.
  • Therapeutic resistance remains a major challenge in advanced-stage NSCLC.

Purpose of the Study:

  • To review mechanisms of resistance to targeted therapies in NSCLC.
  • To explore on-target and off-target resistance pathways.
  • To discuss the role of the tumor microenvironment in therapeutic resistance.

Main Methods:

  • Literature review of targeted therapies and resistance mechanisms in NSCLC.
  • Analysis of common resistance themes across different NSCLC subtypes.
  • Examination of interactions between targeted therapies and the tumor microenvironment.

Main Results:

  • Resistance occurs through on-target alterations in the oncogene or off-target alterations in downstream/parallel pathways.
  • Tumor microenvironment interactions significantly contribute to therapeutic resistance.
  • Common resistance mechanisms are observed across NSCLC subtypes with EGFR, ALK, ROS1, and BRAF alterations.

Conclusions:

  • Understanding resistance mechanisms is crucial for developing effective NSCLC treatments.
  • Combination therapy approaches may overcome resistance and tumor heterogeneity.
  • Further research into resistance pathways can inform novel therapeutic strategies for NSCLC.

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