What type of study is this?

This is a Pre-Registered Trial study (also classified as: Experimental Study).

September 27, 2025

Abstract A028: Identification of biomarkers of response to RAS-RAF-MEK pathway inhibition in RAS-altered rhabdomyosarcoma

Key Points

A 67% objective response rate was achieved in nine rhabdomyosarcoma xenografts treated with combined inhibitors.
Lack of rpS6 inhibition correlated with tumor progression, while MYC suppression sensitized cells to MAPK inhibition.
NRAS mutations, particularly Q61X, G13R, and G12D, were linked with sensitivity to treatment, while G13D showed resistance.
Concurrent NF1 inactivation along with RAS mutation may predict resistance to RAS-RAF-MEK inhibitors.

Abstract

Abstract Alterations in the RAS-RAF-MEK (MAPK) pathway through oncogenic RAS mutations or NF1 inactivation are frequently observed in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children. Inhibiting the MAPK pathway by targeting CRAF and MEK has shown promising activity in H/NRAS Q61-mutated RMS. In this study, we evaluated the preclinical efficacy of the paralog selective B/CRAF inhibitor naporafenib in combination with the MEK inhibitor trametinib in a panel of 9 RMS tumors xenografts spanning diverse H/NRAS codon mutations beyond Q61X, as well as NF1-inactivation, and sought to identify markers of response. Precilinical objective response was 67% (6/9). We performed comparative RNA sequencing analysis and in vivo pharmacodynamic assays in progressive versus sensitive tumor models and determined that neither potency of MAPK pathway inhibition, nor the induction of myogenic differentiation correlated with response, while lack of MYC and S6 ribosomal protein (rpS6) inhibition and increase of oxidative phosphorylation correlated with progressive disease. Using genetic and pharmacologic manipulations, we show that both rpS6 and MYC are required for the growth of rhabdomyosarcoma cells and that suppression of rpS6 and MYC, or inhibition of oxidative phosphorylation, can sensitize cells and tumor xenografts to MAPK inhibition. Further, we show that rhabdomyosarcoma-associated NRAS mutations determine sensitivity to B/CARF + MEK inhibitors combination, with NRAS Q61X, NRAS G13R and NRAS G12D being preferentially sensitive, but NRAS G13D being resistant. In addition, we find that concurrent NF-1 inactivation and RAS mutation could predict resistance. These results highlight the importance of considering genetic makeup and markers of response when selecting RAS-RAF-MEK targeted agents for the treatment of RAS-driven rhabdomyosarcoma. Citation Format: Shreetama Bandyopadhayaya, Natalia Garcia, Funan He, Arnab Sarkar, Katia Campos, Teresa Marple, Paulomi Modi, Siyuan Zheng, Myron Ignatius, Vesselina G. Cooke, Angelina V. Vaseva. Identification of biomarkers of response to RAS-RAF-MEK pathway inhibition in RAS-altered rhabdomyosarcoma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₂): Abstract nr A028.

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