Combined Inhibition of HRAS and MEK Induces Tumor Regression and Restores Myogenic Differentiation in HRAS-Mutant Rhabdomyosarcoma
Year: 2026
Type: article
Abstract: 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 (FTI), 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. In this study, 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 RAS. The combination of HRAS suppression with FTI and MEK inhibition impaired ERK reactivation and reduced ERK transcriptional output in HRAS-mutant RMS models. Cotargeting 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. SIGNIFICANCE: Farnesyltransferase and MEK inhibition suppresses ERK reactivation, decreases tumor growth, and promotes myogenesis in HRAS-mutant rhabdomyosarcoma.
Source: Cancer Research
Authors: Patience Odeniyide, Alyza Skaist, Elizabeth Fenner, Hanah Amirkhanian, Andrew Baker, Alla Lisok, Lindy Zhang, Lisa B. Fridman, Rafael I. Rojas, Katie E. Hebron, Christopher Davis, Xiaohu Zhang, Gabrielle Feldman, Steven P. Angus, Craig J. Thomas, Angelina V. Vaseva, Marielle E. Yohe, Elana J. Fertig, Christine A. Pratilas
Institutions: Johns Hopkins University, Johns Hopkins Medicine, Sidney Kimmel Comprehensive Cancer Center, Frederick National Laboratory for Cancer Research, Center for Cancer Research, Indiana University Health, Indiana University Hospital, Riley Hospital for Children, Indiana University School of Medicine, Indiana University – Purdue University Indianapolis, National Institutes of Health, National Center for Advancing Translational Sciences, National Cancer Institute, Oregon Health & Science University, OHSU Knight Cancer Institute, University of Maryland, Baltimore, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Kura Oncology, V Foundation for Cancer Research, 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, Children's Cancer Foundation
Awards: G1143455775, G1165598027, Mays Cancer Center at UT Health SA, G1258574971, G1610190245, Illumina NovaSeq 6000 Sequencing System, G3318661017, G465951118, G5827286289, Center for Innovative Drug Discovery: Expansion of a Highly Productive Shared Cancer Drug Discovery Resource for Texas, G6743030886, PURPOSE:THE PURPOSE OF THIS GRANT IS TO PROCURE EQUIPMENT AND DATA LIBRARIES IN SUPPORT OF THE UNIVERSITY OF TEXAS HEALTH SCIENCES CENTER AT SAN ANTONIO?S CENTER FOR INNOVATIVE DRUG DISCOVERY (CIDD). THIS CENTER SEEKS TO FIND NOVEL TREATMENTS FOR INCURABLE DISEASES, INCLUDING NONALCOHOLIC HEPATIC STEATOSIS OR FATTY LIVER DISEASE, WHICH IS EPIDEMIC IN SOUTH TEXAS AMONG ITS HISPANIC POPULATION. THE CAPABILITIES FUNDED IN THIS GRANT WILL BE USED TO SUPPORT ONGOING RESEARCH EFFORTS RELATED TO THE DETERMINATION OF APPROPRIATE INHIBITORS FOR FATTY LIVER DISEASE, WHILE ALSO PROVIDING THE TOOLS NEEDED TO ADDRESS MANY OTHER CURRENTLY INCURABLE DISEASES AFFECTING RESIDENTS IN TEXAS AND ACROSS THE U.S.ACTIVITIES TO BE PERFORMED:THIS GRANT WILL INCLUDE THE LEASING AND DIRECT PROCUREMENT OF KEY EQUIPMENT NEEDED TO CONDUCT RESEARCH TOWARD DRUG DISCOVERY AND TO TRAIN CURRENT AND FUTURE STUDENTS AT THE UNIVERSITY OF TEXAS HEALTH SCIENCES CENTER IN THE PROPER CHARACTERIZATION OF CELLS AND TISSUES AND EVALUATION OF BIOLOGICAL SAMPLES THROUGH ADVANCED TOOLS SUCH AS CRYO-TEM. PROCUREMENTS WILL INCLUDE CHEMICAL DATA LIBRARIES (FOR DRUG DISCOVERY), LEASING OF A CRYO-TEM, AND ADVANCED TOOLS FOR STABILITY CHARACTERIZATION, DETERMINING BIOMOLECULAR INTERACTIONS, AND CULTURING CELLS AND TISSUES.EXPECTED OUTCOMES:THE EQUIPMENT AND SOFTWARE LIBRARIES PROCURED IN THIS GRANT WILL HAVE A DIRECT EFFECT ON ONGOING RESEARCH IN DRUG DISCOVERY AT THE CIDD. WHILE THE INITIAL USE OF THESE TOOLS WILL SUPPORT RESEARCH TOWARD TREATMENTS FOR HEPATIC STEATOSIS, THESE CAPABILITIES WILL ALSO ENABLE RESEARCH AND TRAINING RELATIVE TO DRUG DISCOVERY ACROSS A WIDE RANGE OF CURRENTLY UNTREATABLE DISEASES.INTENDED BENEFICIARIES:INTENDED BENEFICIARIES FROM THIS GRANT WILL INCLUDE CURRENT AND FUTURE STUDENTS AND FACULTY AT THE CIDD, ALONG WITH A PLETHORA OF INDUSTRIAL AND OTHER ACADEMIC COLLABORATORS ADDRESSING THE FIELD OF DRUG DISCOVERY. SPECIFIC TO THE PRIMARY TARGET APPLICATION OF FATTY LIVER DISEASE, THE HISPANIC POPULATION IN SOUTH TEXAS WILL BE ONE OF THE KEY INTENDED BENEFICIARIES, ALONG WITH THOSE SUFFERING FROM MANY OTHER DISEASES.SUBRECIPIENT ACTIVITIES:THE RECIPIENT DOES NOT INTEND TO SUBAWARD FUNDS., G8345979365, UTHSCSA Cancer Genome Sequencing and Computation Core, G9000041231, G9000066787, G9000324485
OpenAlex ID: W7128611810
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