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Ref Type Journal Article
PMID (34737198)
Authors Garcia N, Del Pozo V, Yohe ME, Goodwin CM, Shackleford TJ, Wang L, Baxi K, Chen Y, Rogojina AT, Zimmerman SM, Peer CJ, Figg WD, Ignatius MS, Wood KC, Houghton PJ, Vaseva AV
Title Vertical Inhibition of the RAF-MEK-ERK Cascade Induces Myogenic Differentiation, Apoptosis, and Tumor Regression in H/NRASQ61X Mutant Rhabdomyosarcoma.
Journal Molecular cancer therapeutics
Vol 21
Issue 1
Date 2022 01
URL
Abstract Text Oncogenic RAS signaling is an attractive target for fusion-negative rhabdomyosarcoma (FN-RMS). Our study validates the role of the ERK MAPK effector pathway in mediating RAS dependency in a panel of H/NRASQ61X mutant RMS cells and correlates in vivo efficacy of the MEK inhibitor trametinib with pharmacodynamics of ERK activity. A screen is used to identify trametinib-sensitizing targets, and combinations are evaluated in cells and tumor xenografts. We find that the ERK MAPK pathway is central to H/NRASQ61X dependency in RMS cells; however, there is poor in vivo response to clinically relevant exposures with trametinib, which correlates with inefficient suppression of ERK activity. CRISPR screening points to vertical inhibition of the RAF-MEK-ERK cascade by cosuppression of MEK and either CRAF or ERK. CRAF is central to rebound pathway activation following MEK or ERK inhibition. Concurrent CRAF suppression and MEK or ERK inhibition, or concurrent pan-RAF and MEK/ERK inhibition (pan-RAFi + MEKi/ERKi), or concurrent MEK and ERK inhibition (MEKi + ERKi) all synergistically block ERK activity and induce myogenic differentiation and apoptosis. In vivo assessment of pan-RAFi + ERKi or MEKi + ERKi potently suppress growth of H/NRASQ61X RMS tumor xenografts, with pan-RAFi + ERKi being more effective and better tolerated. We conclude that CRAF reactivation limits the activity of single-agent MEK/ERK inhibitors in FN-RMS. Vertical targeting of the RAF-MEK-ERK cascade and particularly cotargeting of CRAF and MEK or ERK, or the combination of pan-RAF inhibitors with MEK or ERK inhibitors, have synergistic activity and potently suppress H/NRASQ61X mutant RMS tumor growth.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
HRAS Q61K rhabdomyosarcoma sensitive LY3009120 + LY3214996 Preclinical - Cell line xenograft Actionable In a preclinical study, LY3214996 and LY3009120 combination treatment synergistically induced cell cycle arrest and apoptosis in rhabdomyosarcoma cell lines harboring HRAS Q61K in culture and induced tumor growth regression in a xenograft model (PMID: 34737198). 34737198
HRAS Q61K rhabdomyosarcoma no benefit Trametinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited ERK signaling and viability in rhabdomyosarcoma cell lines harboring HRAS Q61K in culture, but did not inhibit ERK signaling in cell line xenograft models and led to tumor progression (PMID: 34737198). 34737198
NRAS Q61L rhabdomyosarcoma sensitive LY3009120 + LY3214996 Preclinical - Cell culture Actionable In a preclinical study, LY3214996 and LY3009120 combination treatment synergistically induced cell cycle arrest and apoptosis in rhabdomyosarcoma cell lines harboring NRAS Q61L in culture (PMID: 34737198). 34737198
NRAS Q61L rhabdomyosarcoma sensitive LY3214996 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) and LY3214996 combination treatment synergistically inhibited growth and induced apoptosis and cell cycle arrest in a rhabdomyosarcoma cell line harboring NRAS Q61L in culture (PMID: 34737198). 34737198
NRAS Q61H rhabdomyosarcoma sensitive LY3009120 + LY3214996 Preclinical - Cell culture Actionable In a preclinical study, LY3214996 and LY3009120 combination treatment synergistically induced cell cycle arrest and apoptosis in rhabdomyosarcoma cell lines harboring NRAS Q61H in culture (PMID: 34737198). 34737198
NRAS Q61H rhabdomyosarcoma sensitive LY3009120 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) and LY3009120 combination treatment synergistically inhibited Erk phosphorylation, proliferation, and colony formation and induced cell cycle arrest and apoptosis in a rhabdomyosarcoma cell line harboring NRAS Q61H in culture (PMID: 34737198). 34737198
HRAS Q61K rhabdomyosarcoma sensitive LY3009120 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) and LY3009120 combination treatment synergistically inhibited Erk phosphorylation, proliferation, and colony formation and induced cell cycle arrest and apoptosis in rhabdomyosarcoma cell lines harboring HRAS Q61K in culture (PMID: 34737198). 34737198
NRAS Q61L rhabdomyosarcoma sensitive LY3009120 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) and LY3009120 combination treatment synergistically inhibited Erk phosphorylation, proliferation, and colony formation and induced cell cycle arrest and apoptosis in a rhabdomyosarcoma cell line harboring NRAS Q61L in culture (PMID: 34737198). 34737198
HRAS Q61K rhabdomyosarcoma sensitive LY3214996 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) and LY3214996 combination treatment synergistically inhibited growth and induced apoptosis and cell cycle arrest in rhabdomyosarcoma cell lines harboring HRAS Q61K in culture and induced tumor regression in a xenograft model (PMID: 34737198). 34737198
NRAS Q61H rhabdomyosarcoma sensitive LY3214996 + Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, Mekinist (trametinib) and LY3214996 combination treatment synergistically inhibited growth and induced apoptosis and cell cycle arrest in a rhabdomyosarcoma cell line harboring NRAS Q61H in culture and delayed tumor growth in a xenograft model (PMID: 34737198). 34737198
NRAS Q61H rhabdomyosarcoma no benefit Trametinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited ERK signaling and viability in rhabdomyosarcoma cell lines harboring NRAS Q61H in culture, but did not inhibit ERK signaling in cell line xenograft models and led to tumor progression (PMID: 34737198). 34737198