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 (<i>Tpo-Cre/Hras^G12V/p53^flox/flox</i> ) 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 <i>in vitro</i> by selective RTK (i.e., EGFR, FGFR) inhibitors, but responses were ineffective <i>in vivo</i>, 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 <i>Nf1</i> nonsense mutation and an activating mutation in <i>Gnas</i> at high allelic frequency, supporting the on-target effects of the drug. Cell lines modified with these genetic lesions recapitulated tipifarnib resistance <i>in vivo</i> This study demonstrates the feasibility of targeting Ras membrane association in cancers <i>in vivo</i> and predicts combination therapies that confer additional benefit.<b>Significance:</b> 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. <i>Cancer Res; 78(16); 4642-57. ©2018 AACR</i>.