Reference Detail

Ref Type
PMID (27009859)
Authors Amin AD, Li L, Rajan SS, Gokhale V, Groysman MJ, Pongtornpipat P, Tapia EO, Wang M, Schatz JH
Title TKI sensitivity patterns of novel kinase-domain mutations suggest therapeutic opportunities for patients with resistant ALK+ tumors.
Journal Oncotarget
Vol
Issue
Date 2016 Mar 18
URL
Abstract Text The anaplastic lymphoma kinase (ALK) protein drives tumorigenesis in subsets of several tumors through chromosomal rearrangements that express and activate its C-terminal kinase domain. In addition, germline predisposition alleles and acquired mutations are found in the full-length protein in the pediatric tumor neuroblastoma. ALK-specific tyrosine kinase inhibitors (TKIs) have become important new drugs for ALK-driven lung cancer, but acquired resistance via multiple mechanisms including kinase-domain mutations eventually develops, limiting median progression-free survival to less than a year. Here we assess the impact of several kinase-domain mutations that arose during TKI resistance selections of ALK+ anaplastic large-cell lymphoma (ALCL) cell lines. These include novel variants with respect to ALK-fusion cancers, R1192P and T1151M, and with respect to ALCL, F1174L and I1171S. We assess the effects of these mutations on the activity of six clinical inhibitors in independent systems engineered to depend on either the ALCL fusion kinase NPM-ALK or the lung-cancer fusion kinase EML4-ALK. Our results inform treatment strategies with a likelihood of bypassing mutations when detected in resistant patient samples and highlight differences between the effects of particular mutations on the two ALK fusions.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
I1171S missense unknown ALK I1171S lies within the protein kinase domain of the Alk protein (UniProt.org). I1171S has been demonstrated to confer drug resistance in the context of ALK fusions in culture (PMID: 27009859, PMID: 25393796), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Jun 2018). Y
I1171T missense gain of function ALK I1171T lies within the protein kinase domain of the Alk protein (UniProt.org). I1171T confers a gain of function on the Alk protein as indicated by ligand-independent autophosphorylation, activation of Erk1/2, and cell transformation (PMID: 29907598), and has been demonstrated to confer drug resistance in the context of ALK fusions in culture (PMID: 27009859). Y
T1151M missense unknown ALK T1151M lies within the protein kinase domain and inhibitor binding region of the Alk protein (UniProt.org). T1151M has been demonstrated to occur as a secondary drug resistance mutation in the context of NPM1-ALK (PMID: 27009859), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Jun 2018). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NPM1-ALK ALK I1171S Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited the growth of transformed cells expressing NPM1-ALK with ALK I1171S in culture (PMID: 27009859). 27009859
EML4-ALK ALK G1269A Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In preclinical studies, Alunbrig (brigatinib) inhibited the growth of transformed cells expressing EML4-ALK with ALK G1269A in culture (PMID: 27009859, PMID: 26698910). 26698910 27009859
NPM1-ALK ALK T1151M anaplastic large cell lymphoma resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK T1151M were resistant to Zykadia (ceritinib) in culture (PMID: 27009859). 27009859
NPM1-ALK ALK R1192P Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited the growth of transformed cells expressing NPM1-ALK with ALK R1192P in culture (PMID: 27009859). 27009859
NPM1-ALK ALK G1269A Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK G1269A were resistant to Alecensa (alectinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK F1174L Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK F1174L were resistant to Xalkori (crizotinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK I1171S Advanced Solid Tumor sensitive AZD3463 Preclinical - Cell culture Actionable In a preclinical study, AZD3463 inhibited the growth of transformed cells expressing NPM1-ALK with ALK I1171S in culture (PMID: 27009859). 27009859
EML4-ALK ALK T1151M Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited the growth of transformed cells expressing EML4-ALK with ALK T1151M in culture (PMID: 27009859). 27009859
NPM1-ALK ALK G1269A Advanced Solid Tumor sensitive ASP3026 Preclinical - Cell culture Actionable In a preclinical study, ASP3026 inhibited the growth of transformed cells expressing NPM1-ALK with ALK G1269A in culture (PMID: 27009859). 27009859
NPM1-ALK ALK I1171S Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171S were resistant to Zykadia (ceritinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
EML4-ALK ALK I1171S Advanced Solid Tumor resistant AZD3463 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171S were resistant to AZD3463 mediated growth inhibition in culture (PMID: 27009859). 27009859
EML4-ALK ALK T1151M Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cell lines harboring EML4-ALK with ALK T1151M were resistant to Zykadia (ceritinib) 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 R1192P Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK R1192P were resistant to ASP3026 mediated growth inhibition in culture (PMID: 27009859). 27009859
EML4-ALK ALK R1192P Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited the growth of transformed cells expressing EML4-ALK with ALK R1192P in culture (PMID: 27009859). 27009859
NPM1-ALK ALK R1192P Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK R1192P were resistant to ASP3026 mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK I1171S Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171S were resistant to Xalkori (crizotinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK T1151M Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK T1151M were resistant to ASP3026 mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK G1269A Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK G1269A were resistant to Zykadia (ceritinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK I1171S anaplastic large cell lymphoma resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK I1161S were resistant to Xalkori (crizotinib) in culture (PMID: 27009859). 27009859
NPM1-ALK ALK T1151M Advanced Solid Tumor resistant AZD3463 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK T1151M were resistant to AZD3463 mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK I1171S Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171S were resistant to ASP3026 mediated growth inhibition in culture (PMID: 27009859). 27009859
EML4-ALK ALK T1151M 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 T1151M in culture (PMID: 27009859). 27009859
NPM1-ALK ALK T1151M Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK T1151M were resistant to Zykadia (ceritinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
EML4-ALK ALK T1151M Advanced Solid Tumor sensitive Alectinib Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) inhibited the growth of transformed cells expressing EML4-ALK with ALK T1151M in culture (PMID: 27009859). 27009859
NPM1-ALK ALK G1269A Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited the growth of transformed cells expressing NPM1-ALK with ALK G1269A in culture (PMID: 27009859). 27009859
EML4-ALK ALK I1171S Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171S were resistant to ASP3026 mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK R1192P anaplastic large cell lymphoma resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK R1192P were resistant to Xalkori (crizotinib) in culture (PMID: 27009859). 27009859
EML4-ALK ALK T1151M Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cell lines harboring EML4-ALK with ALK T1151M were resistant to ASP3026 in culture (PMID: 27009859). 27009859
NPM1-ALK ALK G1269A Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK G1269A were resistant to Xalkori (crizotinib) 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
NPM1-ALK ALK R1192P Advanced Solid Tumor decreased response AZD3463 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK R1192P had a reduced response to AZD3463 mediated growth inhibition in culture compared to cells expressing wild-type NPM1-ALK (PMID: 27009859). 27009859
EML4-ALK ALK G1269A Advanced Solid Tumor conflicting Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1269A were resistant to Alecensa (alectinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
EML4-ALK ALK G1269A Advanced Solid Tumor conflicting Alectinib Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) modestly inhibited growth of transformed cells expression EML4-ALK with ALK G1269A in culture (PMID: 26698910). 26698910
EML4-ALK ALK T1151M Advanced Solid Tumor sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited the growth of transformed cells expressing EML4-ALK with ALK T1151M in culture (PMID: 27009859). 27009859
NPM1-ALK ALK F1174L Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK F1174L were resistant to ASP3026 mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK R1192P Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK R1192P were resistant to Zykadia (ceritinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK F1174L Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK F1174L were resistant to Alecensa (alectinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
EML4-ALK ALK I1171S Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171S were resistant to Alecensa (alectinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK R1192P Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK R1192P were resistant to Alecensa (alectinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK F1174L Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK F1174L were resistant to Zykadia (ceritinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK G1269A Advanced Solid Tumor sensitive AZD3463 Preclinical - Cell culture Actionable In a preclinical study, AZD3463 inhibited the growth of transformed cells expressing NPM1-ALK with ALK G1269A 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 R1192P Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK R1192P were resistant to Zykadia (ceritinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK T1151M Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK T1151M were resistant to Xalkori (crizotinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
EML4-ALK ALK I1171S Advanced Solid Tumor conflicting Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171S were resistant to Zykadia (ceritinib) mediated growth inhibition in culture (PMID: 27009859), however, in another study comparable cells demonstrated sensitivity (PMID: 27432227). 27009859 27432227
NPM1-ALK ALK R1192P Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK R1192P were resistant to Xalkori (Crizotinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK I1171S Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK I1171S were resistant to Alecensa (alectinib) mediated growth inhibition 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 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
NPM1-ALK ALK T1151M Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK T1151M were resistant to Alunbrig (brigatinib)-mediated growth inhibition in culture (PMID: 27009859). 27009859
EML4-ALK ALK R1192P 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 R1192P in culture (PMID: 27009859). 27009859
EML4-ALK ALK F1174L Advanced Solid Tumor resistant Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK F1174L were resistant to Alunbrig (brigatinib)-mediated growth inhibition in culture (PMID: 27009859). 27009859
EML4-ALK ALK G1269A 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 G1269A in culture (PMID: 27009859). 27009859
EML4-ALK ALK I1171S Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171S were resistant to Xalkori (crizotinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
EML4-ALK ALK I1171S Advanced Solid Tumor conflicting Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK I1171S were resistant to Alunbrig (brigatinib)-mediated growth inhibition in culture (PMID: 27009859), however, another study with comparable cells demonstrated sensitivity (PMID: 27432227). 27432227 27009859
EML4-ALK ALK G1269A Advanced Solid Tumor resistant ASP3026 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK G1269A were resistant to ASP3026 mediated growth inhibition in culture (PMID: 27009859). 27009859
NPM1-ALK ALK G1269A anaplastic large cell lymphoma resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK G1269A were resistant to Xalkori (crizotinib) in culture (PMID: 27009859). 27009859
NPM1-ALK ALK F1174L Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited the growth of transformed cells expressing NPM1-ALK with ALK F1174L in culture (PMID: 27009859). 27009859
NPM1-ALK ALK T1151M Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK T1151M were resistant to Alecensa (alectinib) mediated growth inhibition in culture (PMID: 27009859). 27009859
EML4-ALK ALK R1192P Advanced Solid Tumor sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited the growth of transformed cells expressing EML4-ALK with ALK R1192P in culture (PMID: 27009859). 27009859
NPM1-ALK ALK F1174L Advanced Solid Tumor resistant AZD3463 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing NPM1-ALK with ALK F1174L were resistant to AZD3463 mediated growth inhibition in culture (PMID: 27009859). 27009859
EML4-ALK ALK R1192P Advanced Solid Tumor sensitive Alectinib Preclinical - Cell culture Actionable In a preclinical study, Alecensa (alectinib) inhibited growth of transformed cells overexpressing EML4-ALK with ALK R1192P in culture (PMID: 27009859). 27009859
EML4-ALK ALK G1269A Advanced Solid Tumor sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited growth of transformed cells expressing EML4-ALK with ALK G1269A in culture (PMID: 27009859). 27009859
NPM1-ALK ALK F1174L anaplastic large cell lymphoma resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, human anaplastic large cell lymphoma cell lines harboring NPM1-ALK with ALK F1174L were resistant to Zykadia (ceritinib) in culture (PMID: 27009859). 27009859