Related Experiment Video

Updated: Feb 10, 2026

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans
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Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

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The Farnesyl Transferase Inhibitor Darlifarnib (KO-2806) Resensitizes Relapsing Tumors to RAS Inhibition

Hetika Vora Patel1, Alison Elizabeth Smith1, Stacia Chan1

  • 1Kura Oncology, Inc., San Diego, California.

Cancer Research
|February 9, 2026
PubMed

Insights

Persistent mTORC1 activity drives resistance to RAS inhibitors in KRAS-mutant cancers. Combining farnesyl transferase inhibitor darlifarnib (KO-2806) with RAS inhibitors overcomes this resistance, leading to tumor regression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Resistance to RAS-targeting therapies is a major clinical challenge in KRAS-mutant cancers.
  • Nongenetic mechanisms, including persistent mTORC1 activity, contribute to acquired resistance to RAS inhibition.

Purpose of the Study:

  • To investigate the role of persistent mTORC1 activity as a resistance mechanism to RAS inhibitors.
  • To evaluate the efficacy of darlifarnib (KO-2806), a farnesyl transferase inhibitor, in overcoming RAS inhibitor resistance.

Main Methods:

  • Preclinical models of KRAS-mutant non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) were utilized.
  • Tumor response to RAS inhibitors alone, in combination with KO-2806, or sequentially was assessed.
  • mTORC1 activation and its inhibition by KO-2806 were evaluated.

Main Results:

  • Persistent mTORC1 activity was identified as a driver of resistance to RAS inhibitors in preclinical models.
  • Combination therapy with KO-2806 and RAS inhibitors resulted in rapid and durable tumor regression.
  • KO-2806 restored sensitivity to pan-RAS inhibitors in tumors that had progressed on prior RAS-targeted therapy.

Conclusions:

  • mTORC1 is a key mediator of resistance to RAS-targeted therapies.
  • Darlifarnib (KO-2806) is a promising companion inhibitor for RAS-targeted therapy, particularly in patients with prior exposure to RAS inhibitors.

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