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Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers.

Brian R Untch1,2, Vanessa Dos Anjos1, Maria E R Garcia-Rendueles1

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.

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|May 16, 2018
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Farnesyltransferase inhibitors like tipifarnib show promise against HRAS-driven thyroid cancers. Combining tipifarnib with MEK inhibitors overcomes resistance, with NF1 and GNAS mutations identified as key resistance drivers.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • HRAS is a RAS oncoprotein uniquely susceptible to farnesyltransferase inhibitors (FTIs).
  • FTI therapy for HRAS-driven cancers remains clinically underexploited.
  • Thyroid cancers driven by HRAS present a potential target for FTI intervention.

Purpose of the Study:

  • To evaluate the efficacy of the FTI tipifarnib in Hras-driven thyroid cancer models.
  • To investigate mechanisms of resistance to tipifarnib treatment.
  • To identify combination strategies to overcome FTI resistance.

Main Methods:

  • Treatment of mice with Hras-driven thyroid cancer using tipifarnib.
  • Assessment of tumor regression, survival, and resistance mechanisms.
  • In vitro and in vivo testing of combination therapies (tipifarnib with RTK or MEK inhibitors).
  • Whole-exome sequencing of resistant tumors to identify genetic alterations.

Main Results:

  • Tipifarnib treatment led to sustained tumor regression and improved survival in mice.
  • Acquired resistance to tipifarnib was observed, associated with RAS-MAPK pathway reactivation.
  • Combination therapy with the MEK inhibitor AZD6244 significantly improved outcomes compared to monotherapy.
  • NF1 nonsense mutations and GNAS activating mutations were identified as drivers of acquired resistance.

Conclusions:

  • Targeting Ras membrane association with FTIs is a feasible strategy for HRAS-driven cancers.
  • Combination therapy, particularly with MEK inhibitors, can overcome adaptive resistance.
  • NF1 and GNAS mutations are key mechanisms conferring acquired resistance to HRAS inhibition.