Reference Detail

Ref Type

Journal Article

PMID

(36322002)

Authors

Hebron KE, Wan X, Roth JS, Liewehr DJ, Sealover NE, Frye WJE, Kim A, Stauffer S, Perkins OL, Sun W, Isanogle KA, Robinson CM, James A, Awasthi P, Shankarappa P, Luo X, Lei H, Butcher D, Smith R, Edmondson EF, Chen JQ, Kedei N, Peer CJ, Shern JF, Figg WD, Chen L, Hall MD, Difilippantonio S, Barr FG, Kortum RL, Robey RW, Vaseva AV, Khan J, Yohe ME

Title

The combination of trametinib and ganitumab is effective in RAS-mutated PAX-fusion negative rhabdomyosarcoma models.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research			2022 Nov 02	472-487	Clin Cancer Res

URL

Abstract Text

PAX-fusion negative rhabdomyosarcoma (FN RMS) is driven by alterations in the RAS/MAP kinase pathway and is partially responsive to MEK inhibition. Overexpression of IGF1R and its ligands is also observed in FN RMS. Preclinical and clinical studies have suggested that IGF1R is itself an important target in FN RMS. Here, we sought to identify a combination of an MEK1/2 inhibitor and IGF1R inhibitor that would be tolerated in murine models and effective in both cell line and patient derived xenograft models of RAS-mutant FN RMS.Using proliferation and apoptosis assays, we studied the factorial effects of trametinib and ganitumab (AMG 479), a monoclonal antibody with specificity for human and murine IGF1R, in a panel of RAS-mutant FN RMS cell lines. The molecular mechanism of the observed synergy was determined using conventional and capillary immunoassays. The efficacy and tolerability of trametinib/ganitumab was assessed using a panel of RAS-mutated cell-line and patient-derived RMS xenograft models.Treatment with trametinib and ganitumab resulted in synergistic cellular growth inhibition in all cell lines tested and inhibition of tumor growth in four out of six models of RAS-mutant RMS. The combination was well tolerated in tumor-bearing SCID beige mice. Mechanistically, ganitumab treatment prevented the phosphorylation of AKT induced by MEK inhibition alone. Therapeutic response to the combination was observed in models without a mutation in the PI3K/PTEN axis.We demonstrate that combined trametinib and ganitumab is effective in a genomically diverse panel of RAS-mutated FN RMS preclinical models.

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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 PTEN dec exp	rhabdomyosarcoma	sensitive	Ganitumab + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Ganitumab (AMG-479) sensitized a rhabdomyosarcoma cell line harboring HRAS Q61K with low PTEN expression to treatment with Mekinist (trametinib), resulting in reduced cell growth in culture (PMID: 36322002).	36322002
HRAS Q61K	rhabdomyosarcoma	sensitive	Ganitumab + Trametinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Mekinist (trametinib) and Ganitumab (AMG-479) synergistically inhibited growth of rhabdomyosarcoma cell lines harboring HRAS Q61K in culture, and resulted in tumor regression and increased survival compared to either treatment alone in a cell line xenograft model (PMID: 36322002).	36322002
HRAS G13R	rhabdomyosarcoma	sensitive	Ganitumab + Trametinib	Preclinical - Pdx	Actionable	In a preclinical study, Mekinist (trametinib) and Ganitumab (AMG-479) combination treatment resulted in tumor regression and increased progression-free survival in a patient-derived xenograft (PDX) model of rhabdomyosarcoma harboring HRAS G13R (PMID: 36322002).	36322002
NRAS G13R PIK3CA H1047R	rhabdomyosarcoma	resistant	Ganitumab + Trametinib	Preclinical - Pdx	Actionable	In a preclinical study, a patient-derived xenograft (PDX) model of rhabdomyosarcoma harboring NRAS G13R and PIK3CA H1047R was resistant to the Mekinist (trametinib) and Ganitumab (AMG-479) combination treatment (PMID: 36322002).	36322002
NRAS G13D	rhabdomyosarcoma	sensitive	Ganitumab + Trametinib	Preclinical - Pdx	Actionable	In a preclinical study, Mekinist (trametinib) and Ganitumab (AMG-479) combination treatment resulted in tumor regression and increased progression-free survival in a patient-derived xenograft (PDX) model of rhabdomyosarcoma harboring NRAS G13D (PMID: 36322002).	36322002
NRAS Q61H	rhabdomyosarcoma	predicted - sensitive	Ganitumab + Trametinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Mekinist (trametinib) and Ganitumab (AMG-479) synergistically inhibited growth of a rhabdomyosarcoma cell line harboring NRAS Q61H in culture, but did not improve tumor suppression and survival compared to monotherapy in a cell line xenograft model (PMID: 36322002).	36322002
NRAS Q61H PTEN over exp	rhabdomyosarcoma	sensitive	Ganitumab + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Ganitumab (AMG-479) sensitized a rhabdomyosarcoma cell line harboring NRAS Q61H and overexpressing PTEN to treatment with Mekinist (trametinib), resulting in reduced cell growth in culture (PMID: 36322002).	36322002
HRAS Q61K PTEN dec exp	rhabdomyosarcoma	resistant	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, decreasing Pten expression through shRNA knockdown in a rhabdomyosarcoma cell line harboring HRAS Q61K conferred resistance to Mekinist (trametinib) treatment in culture (PMID: 36322002).	36322002