Format

Send to

Choose Destination
Cancer Res. 2018 Aug 15;78(16):4642-4657. doi: 10.1158/0008-5472.CAN-17-1925. Epub 2018 May 14.

Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
3
Pathology Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Marie-Josée & Henry R. Kravis Center for Molecular Oncology and Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Department of Medicine, Weill Cornell Medical College, New York, New York.
7
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
8
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. faginj@mskcc.org.

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.

PMID:
29760048
PMCID:
PMC6095730
DOI:
10.1158/0008-5472.CAN-17-1925
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center