Combined Inhibition of HRAS and MEK Induces Tumor Regression and Restores Myogenic Differentiation in HRAS-Mutant Rhabdomyosarcoma
Hyperactive RAS signaling, induced by mutations in NRAS, HRAS, or KRAS, drives tumorigenesis in most PAX3/7::FOXO1 fusion-negative rhabdomyosarcomas (FN-RMS). Despite the frequency of these mutations, indirect RAS pathway-directed therapies have been ineffective for RAS-driven RMS. Farnesyltransferase (FTase) inhibitors (FTIs), such as tipifarnib, inhibit HRAS membrane localization and blunt RAS effector signaling, leading to an antitumor effect in HRAS-mutant FN-RMS preclinical models. However, the effect is not durable. Here, we investigated the mechanisms of adaptive resistance that limit the activity of FTIs, revealing that response to FTIs was limited by adaptive feedback reactivation of ERK signaling and upregulation of wild-type (WT) RAS. The combination of HRAS suppression with FTI and MEK inhibition (MEKi) impaired ERK reactivation and reduced ERK transcriptional output in HRAS-mutant RMS models. Co-targeting FTase and MEK restrained tumor progression and induced terminal myogenic differentiation. These findings highlight an effective combinatorial strategy and support its preclinical translation for patients with HRAS-mutant RMS.
Authors
- Alla Lisok
- A. Skaist
- Patience Odeniyide (ORCID: https://orcid.org/0000-0002-9783-1657)
- Craig J. Thomas (ORCID: https://orcid.org/0000-0001-9386-9001)
- Marielle E. Yohe (ORCID: https://orcid.org/0000-0001-5356-9426)
- Elana J. Fertig (ORCID: https://orcid.org/0000-0003-3204-342X)
- Andrew Baker (ORCID: https://orcid.org/0000-0002-9369-7702)
- Katie E. Hebron (ORCID: https://orcid.org/0000-0002-4740-8930)
- Lindy Zhang (ORCID: https://orcid.org/0000-0002-3909-9920)
- Elizabeth Fenner
- Lisa B. Fridman
- Hanah Amirkhanian
- Xiaohu Zhang
- Christopher Davis
- Rafael I. Rojas
- Gabrielle Feldman
- Steven P. Angus
- Christine A. Pratilas
Institutions
- University of Maryland, Baltimore (US)
- National Institutes of Health (US)
- University of Indianapolis (US)
- Johns Hopkins University (US)
- Oregon Health & Science University (US)
- Johns Hopkins Medicine (US)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (MY)
- National Center for Advancing Translational Sciences (US)
- Johns Hopkins Hospital (US)
- National Cancer Research Institute (GB)
- Indiana University – Purdue University Indianapolis (US)
- University of Baltimore (US)
Publication Details
- Journal
- Cancer Research
- Published
- 2026-02-11
- DOI
- https://doi.org/10.1158/0008-5472.can-25-2985
- Primary Topic
- FOXO transcription factor regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Rally Foundation
- Cancer Prevention and Research Institute of Texas
- Johns Hopkins University
- University of Texas at Austin
- National Institutes of Health
- National Institute of Standards and Technology
- School of Medicine, Indiana University
- Sidney Kimmel Comprehensive Cancer Center
- National Cancer Institute
- National Center for Advancing Translational Sciences