Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	21	1	2022 01	170-183	Mol Cancer Ther

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
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
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
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	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 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
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 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	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 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
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