Tipifarnib inhibits HRAS-driven dedifferentiated thyroid cancers Journal Article

Authors: Untch, B. R.; Dos Anjos, V.; Garcia-Rendueles, M. E. R.; Knauf, J. A.; Krishnamoorthy, G. P.; Saqcena, M.; Bhanot, U. K.; Socci, N. D.; Ho, A. L.; Ghossein, R.; Fagin, J. A.
Article Title: 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. 2018 American Association for Cancer Research.
Journal Title: Cancer Research
Volume: 78
Issue: 16
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2018-08-15
Start Page: 4642
End Page: 4657
Language: English
DOI: 10.1158/0008-5472.can-17-1925
PROVIDER: scopus
PMCID: PMC6095730
PUBMED: 29760048
Notes: Article -- Export Date: 4 September 2018 -- Source: Scopus
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