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Ref Type Journal Article
PMID (38032104)
Authors Valencia-Sama I, Kee L, Christopher G, Ohh M, Layeghifard M, Shlien A, Hayes MN, Irwin MS
Title SHP2 inhibition with TNO155 increases efficacy and overcomes resistance of ALK inhibitors in neuroblastoma.
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Abstract Text Survival rates among high-risk neuroblastoma patients remain low and novel therapies for recurrent neuroblastomas are required. ALK is commonly mutated in primary and relapsed neuroblastoma tumors and ALK tyrosine kinase inhibitors (TKIs) are promising treatments for ALK-driven neuroblastoma; however, innate or adaptive resistance to single agent ALK-TKIs remain a clinical challenge. Recently, SHP2 inhibitors have been shown to overcome ALK-TKI resistance in lung tumors harboring ALK rearrangements. Here, we have assessed the efficacy of the SHP2 inhibitor TNO155 alone and in combination with the ALK-TKIs crizotinib, ceritinib, or lorlatinib for the treatment of ALK-driven neuroblastoma using in vitro and in vivo models. In comparison to wild-type, ALK-mutant neuroblastoma cell lines were more sensitive to SHP2 inhibition with TNO155. Moreover, treatment with TNO155 and ALK-TKIs synergistically reduced cell growth and promoted inactivation of ALK and MAPK signaling in ALK-mutant neuroblastoma cells. ALK-mutant cells engrafted into larval zebrafish and treated with single agents or dual SHP2/ALK inhibitors showed reduced growth and invasion. In murine ALK-mutant xenografts, tumor growth was likewise reduced or delayed, and survival was prolonged upon combinatorial treatment of TNO155 and lorlatinib. Finally, we show that lorlatinib-resistant ALK-F1174L neuroblastoma cells harbor additional RAS-MAPK pathway alterations and can be re-sensitized to lorlatinib when combined with TNO155 in vitro and in vivo. Our results report the first evaluation of TNO155 in neuroblastoma and suggest that combinatorial inhibition of ALK and SHP2 could be a novel approach to treating ALK-driven neuroblastoma, potentially including the increasingly common tumors that have developed resistance to ALK-TKIs.

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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
TNO155 TNO155 4 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
TNO155 TNO-155|TNO 155 SHP2 Inhibitor 20 TNO155 is an inhibitor of PTPN11 (SHP2), which potentially blocks SHP2 signaling, thereby inhibiting activation of the MAPK pathway and subsequent tumor cell growth (PMID: 38032104, Cancer Res (2022) 82 (12_Supplement): 1054).
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
ALK F1174L neuroblastoma sensitive Ceritinib + TNO155 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of TNO155 and Zykadia (ceritinib) resulted in enhanced inhibition of downstream signaling and invasion and synergistically decreased viability of neuroblastoma cell lines harboring ALK F1174L in culture and led to significantly decreased tumor growth in a cell line xenograft model compared to either agent alone (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK D1091N neuroblastoma predicted - sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) decreased viability of a neuroblastoma cell line harboring ALK D1091N in culture (PMID: 38032104). 38032104
ALK D1091N neuroblastoma sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) decreased viability of a neuroblastoma cell line harboring ALK D1091N in culture (PMID: 38032104). 38032104
ALK D1091N neuroblastoma sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) decreased viability of a neuroblastoma cell line harboring ALK D1091N in culture (PMID: 38032104). 38032104
ALK F1174L neuroblastoma sensitive Ceritinib Preclinical - Cell line xenograft Actionable In a preclinical study, Zykadia (ceritinib) inhibited downstream signaling and viability in neuroblastoma cell lines harboring ALK F1174L in culture and reduced cell invasion in a cell line xenograft model (PMID: 38032104). 38032104
ALK F1174L neuroblastoma sensitive Crizotinib + TNO155 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of TNO155 and Xalkori (crizotinib) synergistically decreased viability of neuroblastoma cell lines harboring ALK F1174L in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive SHP099 Preclinical - Cell culture Actionable In a preclinical study, SHP099 decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive TNO155 Preclinical - Cell culture Actionable In a preclinical study, TNO155 decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Crizotinib + SHP099 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of SHP099 and Xalkori (crizotinib) synergistically decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK F1174L neuroblastoma sensitive TNO155 Preclinical - Cell line xenograft Actionable In a preclinical study, TNO155 decreased viability and invasion of neuroblastoma cell lines harboring ALK F1174L in culture and decreased tumor growth and cell invasion and increased survival in cell line xenograft models (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Lorlatinib + SHP099 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of SHP099 and Lorbrena (lorlatinib) synergistically decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Lorlatinib + TNO155 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of TNO155 and Lorbrena (lorlatinib) synergistically decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK F1174L neuroblastoma sensitive SHP099 Preclinical - Cell culture Actionable In a preclinical study, SHP099 decreased viability of neuroblastoma cell lines harboring ALK F1174L in culture (PMID: 38032104). 38032104
ALK F1174L neuroblastoma sensitive Ceritinib + SHP099 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of SHP099 and Zykadia (ceritinib) decreased invasion and synergistically decreased viability of neuroblastoma cell lines harboring ALK F1174L in culture (PMID: 38032104). 38032104
ALK F1174L neuroblastoma sensitive Crizotinib + SHP099 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of SHP099 and Xalkori (crizotinib) synergistically decreased viability of neuroblastoma cell lines harboring ALK F1174L in culture (PMID: 38032104). 38032104
ALK F1174L neuroblastoma conflicting Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) treatment inhibited viability of neuroblastoma cell lines harboring ALK F1174L in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Crizotinib + TNO155 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of TNO155 and Xalkori (crizotinib) synergistically decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Ceritinib + TNO155 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of TNO155 and Zykadia (ceritinib) synergistically decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK F1174L neuroblastoma predicted - sensitive Lorlatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Lorbrena (lorlatinib) inhibited downstream signaling, viability, and invasion in neuroblastoma cell lines harboring ALK F1174L in culture, and decreased tumor growth and increased survival in cell line xenograft models (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma sensitive Ceritinib + SHP099 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of SHP099 and Zykadia (ceritinib) synergistically decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104
ALK F1174L neuroblastoma sensitive Lorlatinib + SHP099 Preclinical - Cell culture Actionable In a preclinical study, treatment with the combination of SHP099 and Lorbrena (lorlatinib) decreased invasion and synergistically decreased viability of neuroblastoma cell lines harboring ALK F1174L in culture (PMID: 38032104). 38032104
ALK F1174L neuroblastoma sensitive Lorlatinib + TNO155 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of TNO155 and Lorbrena (lorlatinib) inhibited downstream signaling and invasion and synergistically decreased viability of neuroblastoma cell lines harboring ALK F1174L in culture, decreased growth and improved survival compared to either agent alone in cell line xenograft models, and treatment with TNO155 restored sensitivity to Lorbrena (lorlatinib) in Lorbrena (lorlatinib)-resistant cell lines and cell line xenograft models (PMID: 38032104). 38032104
ALK R1275Q neuroblastoma conflicting Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) decreased viability of neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 38032104). 38032104