Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers.

Abstract

Of the three RAS oncoproteins, only HRAS is delocalized and inactivated by farnesyltransferase inhibitors (FTI), an approach yet to be exploited clinically. In this study, we treat mice bearing Hras-driven poorly differentiated and anaplastic thyroid cancers (Tpo-Cre/HrasG12V/p53flox/flox ) with the FTI tipifarnib. Treatment caused sustained tumor regression and increased survival; however, early and late resistance was observed. Adaptive reactivation of RAS-MAPK signaling was abrogated in vitro by selective RTK (i.e., EGFR, FGFR) inhibitors, but responses were ineffective in vivo, whereas combination of tipifarnib with the MEK inhibitor AZD6244 improved outcomes. A subset of tumor-bearing mice treated with tipifarnib developed acquired resistance. Whole-exome sequencing of resistant tumors identified a Nf1 nonsense mutation and an activating mutation in Gnas at high allelic frequency, supporting the on-target effects of the drug. Cell lines modified with these genetic lesions recapitulated tipifarnib resistance in vivo This study demonstrates the feasibility of targeting Ras membrane association in cancers in vivo and predicts combination therapies that confer additional benefit.Significance: Tipifarnib effectively inhibits oncogenic HRAS-driven tumorigenesis and abrogating adaptive signaling improves responses. NF1 and GNAS mutations drive acquired resistance to Hras inhibition, supporting the on-target effects of the drug. Cancer Res; 78(16); 4642-57. ©2018 AACR.

• Authors: Brian R Untch, Vanessa Dos Anjos, Maria E R Garcia-Rendueles, Jeffrey A Knauf, Gnana P Krishnamoorthy, Mahesh Saqcena, Umeshkumar K Bhanot, Nicholas D Socci, Alan L Ho, Ronald Ghossein, James A Fagin
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 16 Pg. 4642-4657 (08 15 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29760048 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• AZD 6244
• Benzimidazoles
• Chromogranins
• NF1 protein, human
• Neurofibromin 1
• Quinolones
• GNAS protein, human
• GTP-Binding Protein alpha Subunits, Gs
• HRAS protein, human
• Proto-Oncogene Proteins p21(ras)
• tipifarnib

Topics

• Animals
• Benzimidazoles (administration & dosage)
• Carcinogenesis (drug effects)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromogranins (genetics)
• GTP-Binding Protein alpha Subunits, Gs (genetics)
• Humans
• Mice
• Mutation
• Neurofibromin 1 (genetics)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Quinolones (administration & dosage)
• Thyroid Neoplasms (drug therapy, genetics, pathology)
• Xenograft Model Antitumor Assays