Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, Variants, or PubMed publications.

Have questions, comments, or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type Journal Article
PMID (25749034)
Authors Mologni L, Ceccon M, Pirola A, Chiriano G, Piazza R, Scapozza L, Gambacorti-Passerini C
Title NPM/ALK mutants resistant to ASP3026 display variable sensitivity to alternative ALK inhibitors but succumb to the novel compound PF-06463922.
URL
Abstract Text ALK is involved in the onset of several tumors. Crizotinib (XalkoriTM), a potent ALK inhibitor, represents the current front-line treatment for ALK+ NSCLC and shows great clinical efficacy. However, resistant disease often develops after initial response. ASP3026 is a novel second-generation ALK inhibitor with activity on crizotinib-resistant ALK-L1196M gatekeeper mutant. As resistance is likely to be a relevant hurdle for any drug, we sought to determine the resistance profile of ASP3026 in the context of NPM/ALK+ ALCL. We selected six ASP3026-resistant cell lines by culturing human ALCL cells in the presence of increasing concentrations of drug. The established resistant cell lines carry several point mutations in the ALK kinase domain (G1128S, C1156F, I1171N/T, F1174I, N1178H, E1210K and C1156F/D1203N were the most frequent) that are shown to confer resistance to ASP3026 in the Ba/F3 cell model. All mutants were profiled for cross-resistance against a panel of clinically relevant inhibitors including ceritinib, alectinib, crizotinib, AP26113 and PF-06463922. Finally, a genetically heterogeneous ASP3026-resistant cell line was exposed to second-line treatment simulations with all inhibitors. The population evolved according to relative sensitivity of its mutant subclones to the various drugs. Compound PF-06463922 did not allow the outgrowth of any resistant clone, at non-toxic doses.

Filtering

  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. 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 on a longer phrase with spaces (i.e. "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.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
ALK NCBI ALK1|CD246|NBLST3 ALK, anaplastic lymphoma kinase, is a receptor in the insulin receptor superfamily and is a key regulator of neuronal development (PMID: 21502284) and also promotes cell proliferation through activation of MAPK and PI3K signaling pathways (PMID: 27573755). Alk activating mutations, rearrangements, and fusions have been identified in various cancers (PMID: 22649787), including EML4-ALK in non-small cell lung cancer (PMID: 30108712, PMID: 30194140), and a number of mutations confer resistance in the context of Alk fusions (PMID: 25749034, PMID: 21948233). Oncogene
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ALK C1156F missense unknown ALK C1156F lies within the protein kinase domain of the Alk protein (UniProt.org). C1156F has been demonstrated to occur as a secondary drug resistance mutation in the context of NPM1-ALK (PMID: 25749034, PMID: 30322862) and other Alk rearrangements (PMID: 36203454), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Nov 2022). Y
ALK G1128S missense unknown ALK G1128S lies within the protein kinase domain of the Alk protein (UniProt.org). G1128S has been demonstrated to occur as a secondary drug resistance mutation in the context of NPM1-ALK (PMID: 25749034), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Nov 2023). Y
ALK L1196Q missense unknown ALK L1196Q lies within the protein kinase domain of the Alk protein (UniProt.org). L1196Q has been demonstrated to confer resistance to Alk inhibitors in the context of ALK rearrangements (PMID: 23239810, PMID: 25749034, PMID: 33209633), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Aug 2023). Y
ALK N1178H missense unknown ALK N1178H lies within the protein kinase domain of the Alk protein (UniProt.org). N1178H has been demonstrated to occur as a secondary drug resistance mutation in the context of NPM1-ALK (PMID: 25749034), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Dec 2023). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References