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Updated: Dec 21, 2025

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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Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures

Robert Vander Velde1,2, Nara Yoon3, Viktoriya Marusyk1

  • 1Department of Cancer Physiology, H Lee Moffitt Cancer Centre and Research Institute, Tampa, FL, USA.

Nature Communications
|May 16, 2020
PubMed

Insights

Tumor resistance to targeted cancer therapies evolves gradually through multiple genetic and epigenetic changes, not single events. This evolving resistance may offer new therapeutic opportunities through collateral sensitivities.

Area of Science:

  • Oncology
  • Cancer Biology
  • Evolutionary Medicine

Background:

  • Targeted therapies show high initial efficacy but eventually fail in advanced cancers due to tumor resistance and relapse.
  • Limited understanding exists on the evolutionary processes driving cancer drug resistance, despite extensive research on resistance mechanisms.

Purpose of the Study:

  • To investigate the evolutionary pathways of resistance to anaplastic lymphoma kinase (ALK) inhibitors in a preclinical model of ALK-positive non-small cell lung cancer (NSCLC).
  • To elucidate the mechanisms and dynamics of resistance evolution in response to different ALK inhibitors.

Main Methods:

  • Utilized an experimental model of ALK-positive non-small cell lung cancer (NSCLC).
  • Analyzed the emergence and characteristics of resistant subpopulations under selective pressure from various ALK inhibitors.

Main Results:

  • Resistance originated from heterogeneous, weakly resistant subpopulations with differential sensitivity to ALK inhibitors.
  • Observed a hybrid scenario of resistance evolution, involving gradual, multifactorial adaptation through cooperating genetic and epigenetic changes, rather than a single stochastic event.
  • Identified temporally restricted collateral sensitivities in adapting tumor cells, which were absent in naive or fully resistant cells.

Conclusions:

  • Cancer drug resistance evolves through a complex, multifactorial adaptive process.
  • Temporally restricted collateral sensitivities during resistance evolution present potential targets for novel therapeutic strategies against resistant cancers.

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