2. Academic Validation
  3. Combined Inhibition of HRAS and MEK Induces Tumor Regression and Restores Myogenic Differentiation in HRAS-Mutant Rhabdomyosarcoma

Combined Inhibition of HRAS and MEK Induces Tumor Regression and Restores Myogenic Differentiation in HRAS-Mutant Rhabdomyosarcoma

  • Cancer Res. 2026 May 15;86(10):2508-2521. doi: 10.1158/0008-5472.CAN-25-2985.
Patience Odeniyide 1 2,  Alyza Skaist 1,  Elizabeth Fenner 1,  Hanah Amirkhanian 1,  Andrew Baker 1,  Alla Lisok 1,  Lindy Zhang 1 2,  Lisa B Fridman 1,  Rafael I Rojas 1,  Katie E Hebron 3,  Christopher Davis 4,  Xiaohu Zhang 5,  Gabrielle Feldman 5,  Steven P Angus 4,  Craig J Thomas 5 6,  Angelina V Vaseva 7,  Marielle E Yohe 3,  Elana J Fertig 1 8 9 10,  Christine A Pratilas 1 2
Affiliations

Affiliations

  • 1 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • 2 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • 3 Laboratory of Cell and Developmental Signaling, Center for Cancer Research, Frederick, Maryland.
  • 4 Division of Hematology/Oncology, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children at Indiana University Health and Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana.
  • 5 Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland.
  • 6 Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  • 7 Department of Pediatrics, Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
  • 8 Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland.
  • 9 Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.
  • 10 Division of Hematology/Oncology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
PMID: 41671396 DOI: 10.1158/0008-5472.CAN-25-2985
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.

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