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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

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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_004304.5 chr2:g.29220831A>G c.3520T>C p.F1174L RefSeq GRCh38/hg38
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

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK F1174L TP53 wild-type neuroblastoma sensitive Crizotinib + Cyclophosphamide + Topotecan Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Xalkori (crizotinib), Topotecan, and Cytoxan (cyclophosphamide) synergized to sustain tumor regression in xenograft models of a crizotinib-resistant human neuroblastoma cell line harboring ALK F1174L and wild-type TP53 (PMID: 26438783). 26438783
ALK F1174L TP53 wild-type neuroblastoma sensitive Idasanutlin + TAE684 Case Reports/Case Series Actionable In a preclinical study, TAE684 and Idasanutlin (RG7388) synergistically inhibited growth and induced apoptosis in a TP53 wild-type neuroblastoma cell line harboring ALK F1174L in culture (PMID: 36602782). 36602782
ALK F1174L TP53 wild-type neuroblastoma sensitive Alectinib + Idasanutlin Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) and Idasanutlin (RG7388) synergistically inhibited growth and induced apoptosis in a TP53 wild-type neuroblastoma cell line harboring ALK F1174L in culture (PMID: 36602782). 36602782
ALK F1174L TP53 wild-type neuroblastoma sensitive Ceritinib + CGM097 Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Zykadia (ceritinib) and CGM097 inhibited Alk signaling and resulted in synergistic inhibition of proliferation in a TP53 wild-type neuroblastoma cell line harboring ALK F1174L in culture and induced tumor regression in a cell line xenograft model (PMID: 28425916). 28425916
EML4 - ALK ALK F1174L Advanced Solid Tumor conflicting Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ALK F1174L in the context of EML4-ALK demonstrated reduced sensitivity to Xalkori (crizotinib) in culture (PMID: 27780853). 27780853
EML4 - ALK ALK F1174L Advanced Solid Tumor conflicting Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited growth of transformed cells expressing EML4-ALK with ALK F1174L in culture (PMID: 27009859). 27009859
EML4 - ALK ALK F1174L Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK F1174L were resistant to Zykadia (ceritinib)-mediated growth inhibition in culture (PMID: 27009859). 27009859
EML4 - ALK ALK F1174L Advanced Solid Tumor sensitive Alectinib Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) inhibited growth of transformed cells expressing EML4-ALK with ALK F1174L in culture (PMID: 27009859). 27009859
EML4 - ALK ALK F1174L Advanced Solid Tumor sensitive Alectinib Preclinical - Cell line xenograft Actionable In a preclinical study, Alecensa (alectinib) inhibited growth of transformed cells expressing EML4-ALK with ALK F1174L in culture and in xenograft models (PMID: 24887559). 24887559
EML4 - ALK ALK F1174L Advanced Solid Tumor conflicting Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) treatment inhibited viability of transformed cells expressing EML4-ALK with ALK F1174L in culture (PMID: 35421578). 35421578
EML4 - ALK ALK F1174L Advanced Solid Tumor conflicting Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK F1174L were less sensitive to Alunbrig (brigatinib)-mediated growth inhibition compared to cells expressing EML4-ALK in culture (PMID: 27009859). 27009859
EML4 - ALK ALK F1174L Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK F1174L were resistant to ASP3026 mediated growth inhibition in culture (PMID: 27009859). 27009859
EML4 - ALK ALK F1174L Advanced Solid Tumor sensitive AZD3463 Preclinical - Cell culture Actionable In a preclinical study, AZD3463 inhibited the growth of transformed cells expressing EML4-ALK with ALK F1174L in culture (PMID: 27009859). 27009859
EML4 - ALK ALK F1174L Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) inhibited Alk phosphorylation and cell proliferation of transformed cells over expressing ALK F1174L in the context of EML4-ALK in culture (PMID: 26144315). 26144315
EML4 - ALK ALK F1174L Advanced Solid Tumor predicted - resistant XMU-MP-5 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK F1174L did not demonstrate sensitivity to treatment with XMU-MP-5 in culture (PMID: 34845836). 34845836
EML4 - ALK ALK F1174L Advanced Solid Tumor sensitive Iruplinalkib Preclinical - Cell culture Actionable In a preclinical study, Iruplinalkib (WX-0593) treatment inhibited viability of transformed cells expressing EML4-ALK with ALK F1174L in culture (PMID: 35421578). 35421578
EML4 - ALK ALK F1174L Advanced Solid Tumor sensitive APG-2449 Preclinical - Cell culture Actionable In a preclinical study, APG-2449 inhibited proliferation of a cell line expressing EML4-ALK with ALK F1174L in culture (PMID: 35820889). 35820889
ALK F1174L AXL pos neuroblastoma sensitive Bemcentinib + Ceritinib Preclinical - Cell culture Actionable In a preclinical study, the addition of Bemcentinib (BGB-324) to treatment with Zykadia (ceritinib) increased Zykadia (ceritinib)-induced apoptosis in an AXL-expressing neuroblastoma cell line harboring ALK F1174L in culture (PMID: 25450694). 25450694
ALK F1174L AXL pos neuroblastoma sensitive Bemcentinib + Crizotinib Preclinical - Cell culture Actionable In a preclinical study, the addition of Bemcentinib (BGB-324) to treatment with Xalkori (crizotinib) increased Xalkori (crizotinib)-induced apoptosis in an AXL-expressing neuroblastoma cell line harboring ALK F1174L in culture (PMID: 25450694). 25450694
ALK F1174L ALK L1198P neuroblastoma resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, expression of ALK L1198P in neuroblastoma cells harboring an ALK F1174L mutation resulted in resistance to Xalkori (crizotinib) in culture (PMID: 21948233). 21948233
ALK F1174L ALK L1198P neuroblastoma resistant TAE684 Preclinical - Cell culture Actionable In a preclinical study, expression of ALK L1198P in neuroblastoma cells harboring an ALK F1174L mutation resulted in resistance to TAE684 in culture (PMID: 21948233). 21948233
ALK G1123S ALK F1174L neuroblastoma resistant TAE684 Preclinical - Cell culture Actionable In a preclinical study, expression of ALK G1123S in neuroblastoma cells harboring an ALK F1174L mutation resulted in resistance to TAE684 in culture (PMID: 21948233). 21948233
ALK G1123D ALK F1174L neuroblastoma resistant TAE684 Preclinical - Cell culture Actionable In a preclinical study, expression of ALK G1123D in neuroblastoma cells harboring an ALK F1174L mutation resulted in resistance to TAE684 in culture (PMID: 21948233). 21948233
EML4 - ALK ALK F1174L ALK L1196M Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK F1174L was identified as a compound mutation in transformed cells expressing ALK L1196M in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534). 29650534
ALK F1174L ALK amp neuroblastoma sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited proliferation of neuroblastoma cells harboring ALK amplification and ALK F1174L in culture (PMID: 29907598). 29907598
ALK F1174L ALK amp neuroblastoma sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited proliferation of neuroblastoma cells harboring ALK amplification and ALK F1174L in culture (PMID: 29907598). 29907598
EML4 - ALK ALK F1174L ALK L1198V lung non-small cell carcinoma resistant Brigatinib Case Reports/Case Series Actionable In a clinical study, a non-small cell lung carcinoma patient harboring EML4-ALK progressed while being treated with Alunbrig (brigatinib) and was subsequently found to harbor two resistance mutations, ALK F1174L and ALK L1198V, which were both in cis (PMID: 29636358). 29636358
ALK rearrange ALK F1174L lung non-small cell carcinoma predicted - resistant Lorlatinib Clinical Study - Cohort Actionable In a retrospective study, ALK F1174C/L was identified in 14% (4/29) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received Lorbrena (lorlatinib) treatment (PMID: 31358542). 31358542
ALK rearrange ALK F1174L lung adenocarcinoma predicted - resistant Ceritinib Case Reports/Case Series Actionable In a clinical case study, ALK F1174L was identified in biopsies at disease progression after 4 months of Zykadia (ceritinib) treatment in a patient with lung adenocarcinoma harboring ALK rearrangement (PMID: 31585938). 31585938
ALK rearrange ALK F1174L lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a clinical study, ALK F1174L was identified in a patient with non-small cell lung cancer harboring an ALK rearrangement after progression on second-line Alecensa (alectinib) treatment following Xalkori (crizotinib) resistance (Ann of Oncol (2022) 33 (suppl_7): S448-S554). detail...
EML4 - ALK ALK F1174L ALK G1269A lung adenocarcinoma predicted - resistant Belizatinib Case Reports/Case Series Actionable In a clinical case study, ALK F1174L and ALK G1269A were identified as newly acquired mutations in the pleural effusion from a patient with lung adenocarcinoma harboring an acquired EML4-ALK after his disease progressed on Belizatinib (TSR-011) treatment (PMID: 28434515). 28434515
EML4 - ALK ALK F1174L ALK D1203N ALK G1269A lung adenocarcinoma predicted - resistant Ceritinib Case Reports/Case Series Actionable In a clinical case study, ALK D1203N were identified as a newly acquired mutation in the pleural effusion from a patient with lung adenocarcinoma after his disease progressed on Zykadia (ceritinib) treatment, in addition to the EML4-ALK, ALK F1174L, and ALK G1269A acquired after disease progression on Xalkori (crizotinib) and Belizatinib (TSR-011) sequentially (PMID: 28434515). 28434515
ALK rearrange ALK F1174L ALK G1202R lung non-small cell carcinoma predicted - resistant Lorlatinib Case Reports/Case Series Actionable In a clinical case study, a patient with ALK-rearranged non-small cell lung cancer progressed on treatment with Lorbrena (lorlatinib) and subsequent testing of the tumor biopsy revealed ALK G1202R and ALK F1174L whereas testing of single isolated circulating tumor cells (CTC) revealed ALK G1202R and ALK F1174C in one CTC sample and ALK G1202R and ALK T1151M in the second CTC sample (PMID: 31439588). 31439588
ALK F1174L ALK pos lung non-small cell carcinoma predicted - sensitive Ensartinib Case Reports/Case Series Actionable In a Phase II clinical trial, Ensartinib (X-396) treatment resulted in an objective response in 71% (5/7, all partial responses) of patients with ALK-positive non-small cell lung cancer harboring ALK F1174L (n=5) or ALK F1174V (n=1) (PMID: 31628085; NCT0321569). 31628085
EML4 - ALK ALK T1151M ALK C1156Y ALK F1174L ALK G1202R ALK S1206F ALK G1269A lung adenocarcinoma predicted - resistant Lorlatinib Case Reports/Case Series Actionable In a clinical case study, Lorbrena (lorlatinib) treatment resulted in disease progression after 3.7 months therapy in a patient with lung adenocarcinoma harboring EML4-ALK and ALK G1202R, at disease progression, ALK F1174L in cis wth ALK G1202R was identified in biopsies, and ALK C1156Y, G1269A, S1206F, and T1151M were identified in ctDNA (PMID: 31585938). 31585938
EML4 - ALK ALK F1174L ALK G1202R Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ALK F1174L and ALK G1202R compound mutation in the context of EML4-ALK were resistant to Lorbrena (lorlatinib) in culture (PMID: 31585938). 31585938
EML4 - ALK ALK I1171N ALK F1174L Advanced Solid Tumor sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) inhibited viability of transformed cells expressing EML4-ALK with ALK I1171N and F1174L in culture (PMID: 33627640). 33627640
EML4 - ALK ALK I1171N ALK F1174L Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited viability of transformed cells expressing EML4-ALK with ALK I1171N and F1174L in culture (PMID: 33627640). 33627640
EML4 - ALK ALK I1171N ALK F1174L Advanced Solid Tumor resistant Entrectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N and F1174L were resistant to treatment with Rozlytrek (entrectinib) in culture (PMID: 33627640). 33627640
EML4 - ALK ALK I1171N ALK F1174L Advanced Solid Tumor sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited viability of transformed cells expressing EML4-ALK with ALK I1171N and F1174L in culture (PMID: 33627640). 33627640
EML4 - ALK ALK I1171N ALK F1174L Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N and F1174L were resistant to treatment with Alecensa (alectinib) in culture (PMID: 33627640). 33627640
EML4 - ALK ALK I1171N ALK F1174L Advanced Solid Tumor predicted - resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171N and F1174L demonstrated resistance to treatment with Xalkori (crizotinib) in culture (PMID: 33627640). 33627640
EML4 - ALK ALK I1171N ALK F1174L Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) inhibited viability of transformed cells expressing EML4-ALK with ALK I1171N and F1174L in culture (PMID: 33627640). 33627640
ALK F1174L ALK R1275Q neuroblastoma predicted - sensitive 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, and a patient harboring both ALK F1174L and ALK R1275Q stayed on treatment for 3 cycles until disease progression (PMID: 33568345; NCT00939770). 33568345
EML4 - ALK ALK E1129V ALK I1171T ALK F1174C ALK F1174L ALK F1174V ALK G1269A lung adenocarcinoma predicted - resistant Crizotinib Case Reports/Case Series Actionable In a clinical case study, ALK E1129V, F1174C, F1174L, F1174V, I1171T, and G1269A were identified in the post-progression biopsy of a patient with metastatic lung adenocarcinoma harboring EML4-ALK (e13:e20), who previously responded to Xalkori (crizotinib) treatment (PMID: 36093526). 36093526
EML4 - ALK ALK E1129V ALK I1171T ALK F1174C ALK F1174L ALK F1174V ALK G1269A lung adenocarcinoma predicted - sensitive Brigatinib Case Reports/Case Series Actionable In a clinical case study, Alunbrig (brigatinib) treatment resulted in stable disease with a progression-free survival of 10 months in a patient with lung adenocarcinoma harboring EML4-ALK (e13:e20), ALK E1129V, F1174C, F1174L, F1174V, I1171T, and G1269A (PMID: 36093526). 36093526
EML4 - ALK ALK F1174L ALK S1189C lung adenocarcinoma predicted - resistant Crizotinib Case Reports/Case Series Actionable In a clinical case study, a patient with lung adenocarcinoma harboring EML4-ALK along with ALK F1174L in cis with ALK S1189C did not respond to first-line Xalkori (crizotinib) treatment (PMID: 36506539). 36506539
EML4 - ALK ALK F1174L ALK S1189C lung adenocarcinoma predicted - resistant Ceritinib Case Reports/Case Series Actionable In a clinical case study, a patient with lung adenocarcinoma harboring EML4-ALK along with ALK F1174L in cis with ALK S1189C did not respond to second-line Zykadia (ceritinib) treatment (PMID: 36506539). 36506539
EML4 - ALK ALK F1174L ALK E1210K ALK G1269A lung adenocarcinoma predicted - sensitive Lorlatinib Case Reports/Case Series Actionable In a clinical case study, Lorbrena (lorlatinib) treatment resulted in a partial response in a patient with lung adenocarcinoma harboring EML4-ALK (e13:e20), ALK G1269A, ALK F1174L, and ALK E1210K (PMID: 35123209). 35123209
EML4 - ALK ALK I1171T ALK F1174L ALK L1196M ALK D1203N ALK E1210K ALK G1269A lung adenocarcinoma predicted - resistant Lorlatinib Case Reports/Case Series Actionable In a clinical case study, ALK L1196M, D1203N, and I1171T were identified at the time of progression on Lorbrena (lorlatinib) treatment in a patient with lung adenocarcinoma harboring EML4-ALK (e13:e20), ALK G1269A, ALK F1174L, and ALK E1210K (PMID: 35123209). 35123209
ALK F1174L NRAS Q61K neuroblastoma resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, expression of NRAS Q61K in a neuroblastoma cell line harboring ALK F1174L conferred resistance to Zykadia (ceritinib) in culture (PMID: 35689207). 35689207
ALK F1174L NRAS Q61K neuroblastoma resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, expression of NRAS Q61K in a neuroblastoma cell line harboring ALK F1174L conferred resistance to Lorbrena (lorlatinib) in culture (PMID: 35689207). 35689207
ALK F1174L FGFR1 N546K neuroblastoma predicted - resistant Lorlatinib Case Reports/Case Series Actionable In a Phase I trial, a neuroblastoma patient harboring ALK F1174L developed progressive disease on treatment with Lorbrena (lorlatinib) and was found to have acquired FGFR1 N546K via circulating tumor DNA (PMID: 37147298; NCT03107988). 37147298
ALK F1174L PIK3CA H1047R neuroblastoma predicted - resistant Lorlatinib Case Reports/Case Series Actionable In a Phase I trial, a neuroblastoma patient harboring ALK F1174L developed progressive disease on treatment with Lorbrena (lorlatinib) and was found to have acquired PIK3CA H1047R via circulating tumor DNA (PMID: 37147298; NCT03107988). 37147298
ALK F1174L ALK G1202R ALK D1203N ALK amp neuroblastoma predicted - resistant Lorlatinib Case Reports/Case Series Actionable In a Phase I trial, a neuroblastoma patient harboring ALK F1174L developed progressive disease on treatment with Lorbrena (lorlatinib) and was found to have acquired ALK amplification, and ALK G1202R and D1203N each in cis with F1174L via circulating tumor DNA (PMID: 37147298; NCT03107988). 37147298
ALK F1174L ALK L1196M neuroblastoma resistant Lorlatinib Case Reports/Case Series Actionable In a Phase I trial, two neuroblastoma patients harboring ALK F1174L developed progressive disease on treatment with Lorbrena (lorlatinib) and were found to have acquired ALK L1196M via circulating tumor DNA, and a neuroblastoma cell line harboring ALK F1174L and expressing L1196M was resistant to Lorbrena (lorlatinib) in culture (PMID: 37147298; NCT03107988). 37147298
ALK F1174L ALK G1202R neuroblastoma resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, a neuroblastoma cell line harboring ALK F1174L and expressing G1202R was resistant to Lorbrena (lorlatinib) in culture (PMID: 37147298). 37147298
EML4 - ALK ALK F1174L ALK E1210K lung adenocarcinoma predicted - resistant Brigatinib Case Reports/Case Series Actionable In a clinical case study, ALK E1210K was identified at the time of progression on Alunbrig (brigatinib) treatment in a patient with lung adenocarcinoma who initially harbored EML4-ALK (e13:e20) and ALK G1269A, and also acquired ALK F1174L and lost ALK G1269A during Alunbrig (brigatinib) treatment (PMID: 35123209). 35123209