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Gene | ALK |
Variant | F1174L |
Impact List | missense |
Protein Effect | gain of function |
Gene Variant Descriptions | ALK F1174L lies within the protein kinase domain of the Alk protein (UniProt.org). F1174L confers a gain of function to the Alk protein as indicated by transformation activity and increased cell proliferation in culture (PMID: 18923525, PMID: 29533785, PMID: 29907598), and has been demonstrated to occur as a secondary resistance mutation in the context of ALK fusions (PMID: 21030459, PMID: 31452835). |
Associated Drug Resistance | Y |
Category Variants Paths |
ALK mutant ALK act mut ALK F1174L ALK mutant ALK F1174X ALK F1174L |
Transcript | NM_004304.5 |
gDNA | chr2:g.29220831A>G |
cDNA | c.3520T>C |
Protein | p.F1174L |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
NM_004304.4 | chr2:g.29220831A>G | c.3520T>C | p.F1174L | RefSeq | GRCh38/hg38 |
NM_004304 | chr2:g.29220831A>G | c.3520T>C | p.F1174L | RefSeq | GRCh38/hg38 |
NM_004304.5 | chr2:g.29220831A>G | c.3520T>C | p.F1174L | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
ALK F1174L | Advanced Solid Tumor | sensitive | Brigatinib | Preclinical - Cell culture | Actionable | In a preclinical study, a transformed cell line expressing ALK F1174L was sensitive to Alunbrig (brigatinib) in culture, resulting in cell growth inhibition (PMID: 27049722). | 27049722 |
ALK F1174L | neuroblastoma | conflicting | Crizotinib | Case Reports/Case Series | Actionable | In a Phase I/II trial (ADVL0912), Xalkori (crizotinib) treatment resulted in an objective response of 15% (3/20) in pediatric patients with relapsed/refractory neuroblastoma harboring ALK activating mutations or amplifications, although all 3 patients harboring ALK F1174L had disease progression after only 1 cycle of treatment (PMID: 33568345; NCT00939770). | 33568345 |
ALK F1174L | neuroblastoma | conflicting | Crizotinib | Case Reports/Case Series | Actionable | In a Phase Ib trial (PROFILE 1013), Xalkori (crizotinib) therapy resulted in stable disease lasting 19 months in a patient with advanced neuroblastoma harboring ALK F1174L (PMID: 29352732; NCT00939770). | 29352732 |
ALK F1174L | neuroblastoma | conflicting | Crizotinib | Preclinical - Pdx & cell culture | Actionable | In a preclinical study, Xalkori (crizotinib) did not inhibit growth of neuroblastoma cells over expressing ALK F1174L in culture, and only delayed tumor growth in patient-derived and cell line xenograft models harboring ALK F1174L (PMID: 26554404). | 26554404 |
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 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 | predicted - sensitive | Lorlatinib | Case Reports/Case Series | Actionable | In a clinical case study, Lorbrena (lorlatinib) treatment resulted in a complete response in 3 of 5 patients and a partial response in 1 of 5 patients with neuroblastoma harboring ALK F1174L (PMID: 37561984). | 37561984 |
ALK F1174L | neuroblastoma | predicted - sensitive | Lorlatinib | Case Reports/Case Series | Actionable | In a clinical case study, Lorbrena (lorlatinib) treatment resulted in a complete response lasting 13 mo in a pediatric patient with metastatic, relapsed neuroblastoma harboring ALK F1174L and PIK3CA C692Ffs*8, who had previously progressed on combination therapy with Xalkori (crizotinib), Cytoxan (cyclophosphamide), and Topotecan (PMID: 34210658). | 34210658 |
ALK F1174L | neuroblastoma | predicted - sensitive | Lorlatinib | Case Reports/Case Series | Actionable | In a clinical case study, Lorbrena (lorlatinib) treatment resulted in a partial response lasting 10 months in a pediatric patient with metastatic neuroblastoma harboring ALK F1174L, along with MYCN amplification (PMID: 39177282). | 39177282 |
ALK F1174L | neuroblastoma | predicted - sensitive | Lorlatinib | Case Reports/Case Series | Actionable | In a clinical case study, Lorbrena (lorlatinib) treatment resulted in stable disease after 4 cycles in a pediatric patient with neuroblastoma harboring ALK F1174L (PMID: 36765519). | 36765519 |
ALK F1174L | neuroblastoma | predicted - sensitive | Lorlatinib | Case Reports/Case Series | Actionable | In a Phase I trial, Lorbrena (lorlatinib) treatment resulted in a minor response with stable disease in a neuroblastoma patient harboring ALK F1174L (PMID: 37147298; NCT03107988). | 37147298 |
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 F1174L | neuroblastoma | predicted - sensitive | Lorlatinib | Preclinical - Pdx & cell culture | Actionable | In a preclinical study, Lorbrena (lorlatinib) inhibited growth of neuroblastoma cells over expressing ALK F1174L in culture, and induced rapid and sustained complete tumor regression in both patient-derived and cell line xenograft models harboring ALK F1174L (PMID: 26554404). | 26554404 |
ALK F1174L | neuroblastoma | predicted - sensitive | Lorlatinib | Preclinical | Actionable | In a preclinical study, Lorbrena (lorlatinib) treatment induced tumor regression in a transgenic mouse model of neuroblastoma harboring ALK F1174L (PMID: 27483357). | 27483357 |
ALK F1174L | neuroblastoma | predicted - sensitive | Lorlatinib | Preclinical - Cell culture | Actionable | In a preclinical study, neuroblastoma cells harboring ALK F1174L were resistant to Lorbrena (lorlatinib) in culture (PMID: 30322862). | 30322862 |
ALK F1174L | neuroblastoma | predicted - sensitive | Lorlatinib | Case Reports/Case Series | Actionable | In a retrospective analysis, Lorbrena (lorlatinib) treatment resulted in partial remission in a neuroblastoma patient harboring ALK F1174L (PMID: 38787533; NCT04477681). | 38787533 |
ALK F1174L | Advanced Solid Tumor | sensitive | Lorlatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Lorbrena (lorlatinib) inhibited foci formation more efficiently than Xalkori (crizotinib) in transformed cells overexpressing ALK F1174L in culture (PMID: 26554404). | 26554404 |
ALK F1174L | Advanced Solid Tumor | sensitive | Lorlatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Lorbrena (lorlatinib) treatment inhibited Alk phosphorylation and viability in transformed cells expressing ALK F1174L in culture (PMID: 27483357). | 27483357 |
ALK F1174L | neuroblastoma | sensitive | Vandetanib | Preclinical | Actionable | In a preclinical study, Caprelsa (vandetanib) treatment resulted in decreased tumor weight in a Mycn-overexpressing neuroblastoma transgenic mouse model with ALK F1174L (corresponds to F1178L in mouse) and subsequent upregulation of Ret (PMID: 24811913). | 24811913 |
ALK F1174L | neuroblastoma | predicted - sensitive | Entrectinib | Case Reports/Case Series | Actionable | In a Phase I/II trial, Rozlytrek (entrectinib) treatment resulted in a complete response in a patient with neuroblastoma harboring ALK F1174L (PMID: 35395680; NCT02650401). | 35395680 |
ALK F1174L | neuroblastoma | sensitive | AZD3463 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, AZD3463 inhibited growth of neuroblastoma cells harboring ALK F1174L in culture, resulted in near complete tumor regression in cell line xenograft models (PMID: 26786851). | 26786851 |
ALK F1174L | neuroblastoma | sensitive | CEP-28122 | Preclinical - Cell culture | Actionable | In a preclinical study, CEP-28122 inhibited growth of neuroblastoma cells harboring ALK F1174L in culture (PMID: 22203728). | 22203728 |
ALK F1174L | neuroblastoma | sensitive | Ceritinib + Ribociclib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination of Zykadia (ceritinib) and Kisqali (ribociclib) synergistically inhibited proliferation and Alk phosphorylation and induced cell cycle arrest in neuroblastoma cell line harboring ALK F1174L in culture, and induced complete tumor regression and increased event-free survival compared to either agent alone (P<0.0001) in a cell line xenograft model (PMID: 27986745). | 27986745 |
ALK F1174L | neuroblastoma | conflicting | Crizotinib + Cyclophosphamide + Topotecan | Case Reports/Case Series | Actionable | In a clinical case study, combination treatment with Xalkori (crizotinib), Cytoxan (cyclophosphamide), and Topotecan resulted in a complete response after 2 cycles in a one pediatric patient, and a clinical response with stable disease lasting 7 months in another pediatric patient with relapsed neuroblastoma harboring ALK F1174L (PMID: 36765519). | 36765519 |
ALK F1174L | neuroblastoma | conflicting | Crizotinib + Cyclophosphamide + Topotecan | Case Reports/Case Series | Actionable | In a clinical case study, combination treatment with Xalkori (crizotinib), Cytoxan (cyclophosphamide), and Topotecan resulted in progressive disease within 1 cycle of therapy in a pediatric patient with metastatic, relapsed neuroblastoma harboring ALK F1174L and PIK3CA C692Ffs*8 (PMID: 34210658). | 34210658 |
ALK F1174L | neuroblastoma | sensitive | Repotrectinib | Preclinical - Cell culture | Actionable | In a preclinical study, Augtyro (repotrectinib) inhibited proliferation of a neuroblastoma cell line harboring ALK F1174L in culture (PMID: 31852910). | 31852910 |
ALK F1174L | Advanced Solid Tumor | sensitive | Repotrectinib | Preclinical - Cell culture | Actionable | In a preclinical study, Augtyro (repotrectinib) decreased Alk phosphorylation and neurite outgrowth in cells expressing ALK F1174L in culture (PMID: 31852910). | 31852910 |
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 | Advanced Solid Tumor | predicted - sensitive | Conteltinib | Preclinical - Biochemical | Actionable | In a preclinical study, Conteltinib (CT-707) inhibited ALK F1174L activity in an in vitro assay (PMID: 36424628). | 36424628 |
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 F1174L | Advanced Solid Tumor | predicted - sensitive | TPX-0131 | Preclinical - Biochemical | Actionable | In a preclinical study, TPX-0131 inhibited kinase activity of ALK F1174L in an in vitro assay (PMID: 34158340). | 34158340 |
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 | sensitive | NVL-655 | Preclinical - Cell culture | Actionable | In a preclinical study, NVL-655 inhibited viability of neuroblastoma cell lines harboring ALK F1174L in culture (PMID: 39269178). | 39269178 |
ALK F1174L | neuroblastoma | sensitive | TQ-B3139 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, TQ-B3139 (CT-711) inhibited proliferation of a neuroblastoma cell line harboring ALK F1174L in culture and inhibited tumor growth in a cell line xenograft model (PMID: 30210922). | 30210922 |
ALK F1174L | neuroblastoma | sensitive | Cyclophosphamide + Doxorubicin + Lorlatinib + Vincristine Sulfate | Preclinical | Actionable | In a preclinical study, the combination of Lorbrena (lorlatinib), Cytoxan (cyclophosphamide), Adriamycin (doxorubicin), and Oncovin (vincristine) resulted in an early tumor response, and improved survival in a genetically engineered mouse model of neuroblastoma harboring ALK F1174L (PMID: 36602782). | 36602782 |
ALK F1174L | neuroblastoma | sensitive | 4SC-205 + Lorlatinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of 4SC-205 and Lorbrena (lorlatinib) inhibited viability to a greater degree than either therapy alone in neuroblastoma cell lines harboring ALK F1174L (PMID: 34709738). | 34709738 |
ALK F1174L | neuroblastoma | sensitive | 4SC-205 + Ceritinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of 4SC-205 and Zykadia (ceritinib) inhibited viability to a greater degree than either therapy alone in neuroblastoma cell lines harboring ALK F1174L (PMID: 34709738). | 34709738 |
ALK F1174L | neuroblastoma | sensitive | CCC-003 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, CCC-003 treatment resulted in decreased cell proliferation and induction of apoptosis in neuroblastoma cell lines harboring ALK F1174L in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 34591871). | 34591871 |
ALK F1174L | Advanced Solid Tumor | sensitive | CCC-003 | Preclinical - Cell culture | Actionable | In a preclinical study, CCC-003 inhibited viability in transformed cells expressing ALK F1174L in culture (PMID: 34591871). | 34591871 |
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 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 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 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 | 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 |