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Gene | ALK |
Variant | F1245C |
Impact List | missense |
Protein Effect | gain of function |
Gene Variant Descriptions | ALK F1245C lies within the protein kinase domain of the Alk protein (UniProt.org). F1245C results in increased downstream signaling and is transforming in cell culture (PMID: 21838707, PMID: 25517749). |
Associated Drug Resistance | Y |
Transcript | NM_004304.4 |
gDNA | chr2:g.29213993A>C |
cDNA | c.3734T>G |
Protein | p.F1245C |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
NM_004304 | chr2:g.29213993A>C | c.3734T>G | p.F1245C | RefSeq | GRCh38/hg38 |
NM_004304.4 | chr2:g.29213993A>C | c.3734T>G | p.F1245C | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
ALK F1245C | neuroblastoma | resistant | Crizotinib | Preclinical - Pdx & cell culture | Actionable | In a preclinical study, Xalkori (crizotinib) did not inhibit growth of neuroblastoma cells over expressing ALK F1245C in culture, and only delayed tumor growth in patient-derived xenograft models harboring ALK F1245C (PMID: 26554404). | 26554404 |
ALK F1245C | Advanced Solid Tumor | sensitive | Brigatinib | Preclinical - Cell culture | Actionable | In a preclinical study, a transformed cell line expressing ALK F1245C was sensitive to Alunbrig (brigatinib) in culture, resulting in cell growth inhibition (PMID: 27049722). | 27049722 |
ALK F1245C | Advanced Solid Tumor | sensitive | Lorlatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Lorlatinib (PF-06463922) inhibited foci formation more efficiently than Xalkori (crizotinib) in transformed cells over expressing ALK F1245C in culture (PMID: 26554404). | 26554404 |
ALK F1245C | Advanced Solid Tumor | predicted - sensitive | TPX-0131 | Preclinical - Biochemical | Actionable | In a preclinical study, TPX-0131 inhibited kinase activity of ALK F1245C in an in vitro assay (PMID: 34158340). | 34158340 |
ALK F1245C | neuroblastoma | sensitive | Lorlatinib | Preclinical - Pdx & cell culture | Actionable | In a preclinical study, Lorlatinib (PF-06463922) inhibited growth of neuroblastoma cells over expressing ALK F1245C in culture, and induced rapid and sustained complete tumor regression in patient-derived xenograft models harboring ALK F1245C (PMID: 26554404). | 26554404 |
ALK F1245C TP53 wild-type | neuroblastoma | sensitive | Crizotinib + Cyclophosphamide + Topotecan | Preclinical - Pdx | Actionable | In a preclinical study, Xalkori (crizotinib) worked synergistically with Topotecan and Cytoxan (cyclophosphamide), resulting in sustained tumor regression in crizotinib-resistant neuroblastoma PDX models harboring ALK F1245C and wild-type Tp53 (PMID: 26438783). | 26438783 |
EML4 - ALK ALK F1245C | lung non-small cell carcinoma | predicted - resistant | Crizotinib | Case Reports/Case Series | Actionable | In a clinical case study, a non-small cell lung cancer patient harboring EML4-ALK variant 3 demonstrated an initial response to treatment with Xalkori (crizotinib), but progressed after 27 months and was found to have acquired ALK F1245C (PMID: 26775591). | 26775591 |
EML4 - ALK ALK F1245C | lung non-small cell carcinoma | sensitive | Ceritinib | Case Reports/Case Series | Actionable | In a clinical case study, a non-small cell lung cancer patient harboring EML4-ALK variant 3 that demonstrated resistance to treatment with Xalkori (crizotinib) after acquisition of ALK F1245C, achieved a complete radiographic response with no evidence of progression at 6 months following treatment with Zykadia (ceritinib) (PMID: 26775591). | 26775591 |
Molecular Profile | Protein Effect | Treatment Approaches |
---|---|---|
ALK F1245C | gain of function | ALK Inhibitor |
ALK F1245C TP53 wild-type | ||
EML4 - ALK ALK F1245C | Ceritinib |