Reference Detail

Ref Type Journal Article
PMID (29650534)
Authors Yoda S, Lin JJ, Lawrence MS, Burke BJ, Friboulet L, Langenbucher A, Dardaei L, Prutisto-Chang K, Dagogo-Jack I, Timofeevski S, Hubbeling H, Gainor JF, Ferris LA, Riley AK, Kattermann KE, Timonina D, Heist RS, Iafrate AJ, Benes CH, Lennerz JK, Mino-Kenudson M, Engelman JA, Johnson TW, Hata AN, Shaw AT
Title Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer.
Journal Cancer discovery
Vol 8
Issue 6
Date 2018 Jun
URL
Abstract Text The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK. Under comparable conditions, N-ethyl-N-nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single ALK mutations. In similar screens with EML4-ALK containing single ALK resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound ALK mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound ALK mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of ALK mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound ALK mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies.Significance: Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound ALK mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance. Cancer Discov; 8(6); 714-29. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663.

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Molecular Profile Treatment Approach
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
I1179V missense unknown ALK I1179V lies within the protein kinase domain of the Alk protein (UniProt.org). I1179V has been demonstrated to occur as a secondary drug resistance mutation in the context of ALK compound mutations (PMID: 29650534), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Jun 2018). Y
L1198H missense unknown ALK L1198H lies within the protein kinase domain of the Alk protein (UniProt.org). L1198H has not been biochemically characterized, however, has been demonstrated to occur as a secondary drug resistance mutation in the context of ALK compound mutations (PMID: 29650534). Y
L1204V missense unknown ALK L1204V lies within the protein kinase domain of the Alk protein (UniProt.org). L1204V has been demonstrated to occur as a secondary drug resistance mutation in the context of ALK compound mutations (PMID: 29650534), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Jun 2018). Y
L1256F missense unknown ALK L1256F lies within the protein kinase domain of the Alk protein (UniProt.org). L1256F has been demonstrated to occur as a secondary drug resistance mutation in the context of ALK compound mutations (PMID: 29650534), 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
EML4-ALK ALK C1156Y ALK F1174C Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK F1174C was identified as a compound mutation in transformed cells expressing ALK C1156Y in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534). 29650534
EML4-ALK ALK L1196M ALK F1174C Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK F1174C 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
EML4-ALK ALK L1196M ALK I1179V Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK I1179V 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
EML4-ALK ALK C1156Y ALK L1256F Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK L1256F was identified as a compound mutation in transformed cells expressing ALK C1156Y in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534). 29650534
EML4-ALK ALK F1174C ALK G1269A Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK G1269A was identified as a compound mutation in transformed cells expressing ALK F1174C in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534). 29650534
ALK rearrange ALK I1171N ALK L1198F non-small cell lung carcinoma resistant Lorlatinib Clinical Study Actionable In a clinical study, a non-small cell lung cancer patient harboring ALK I1171N and L1198F in cis in the context of EML4-ALK demonstrated primary resistance to Lorlatinib (PF-06463922) (PMID: 29650534). 29650534
ALK rearrange ALK E1210K ALK D1203N ALK G1269A non-small cell lung carcinoma resistant Lorlatinib Clinical Study Actionable In a clinical study, ALK G1269A was identified as an acquired mutation in an ALK-positive non-small cell lung cancer patient harboring ALK E1210K and D1203N who developed resistance to Lorlatinib (PF-06463922) after initial response (PMID: 29650534). 29650534
ALK rearrange ALK G1202R ALK L1196M non-small cell lung carcinoma resistant Lorlatinib Clinical Study Actionable In a clinical study, ALK L1196M was identified as an acquired mutation in an ALK-positive non-small cell lung cancer patient harboring ALK G1202R who developed resistance to Lorlatinib (PF-06463922) after initial response (PMID: 29650534). 29650534
ALK rearrange ALK G1202R ALK G1269A ALK L1204V non-small cell lung carcinoma resistant Lorlatinib Clinical Study Actionable In a clinical study, ALK G1269A and L1204V were identified as acquired mutations in an ALK-positive non-small cell lung cancer patient harboring ALK G1202R who developed resistance to Lorlatinib (PF-06463922) after initial response (PMID: 29650534). 29650534
EML4-ALK ALK L1196M ALK L1256F Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK L1256F 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
EML4-ALK ALK L1196M ALK G1202R Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK L1196M was identified as a compound mutation in transformed cells expressing ALK G1202R in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534). 29650534
EML4-ALK ALK L1196M ALK F1174V Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK F1174V 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
EML4-ALK ALK G1269A ALK L1196M Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK L1196M was identified as a compound mutation in transformed cells expressing ALK G1269A in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534). 29650534
EML4-ALK ALK C1156Y ALK D1203N Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK D1203N was identified as a compound mutation in transformed cells expressing ALK C1156Y in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534). 29650534
EML4-ALK ALK C1156Y ALK G1269A Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK G1269A was identified as a compound mutation in transformed cells expressing ALK C1156Y in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534). 29650534
EML4-ALK ALK G1269A ALK I1171N Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK I1171N was identified as a compound mutation in transformed cells expressing ALK G1269A in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534). 29650534
EML4-ALK ALK C1156Y ALK F1174V Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK F1174V was identified as a compound mutation in transformed cells expressing ALK C1156Y in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534). 29650534
EML4-ALK ALK C1156Y ALK F1174I Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK F1174I was identified as a compound mutation in transformed cells expressing ALK C1156Y in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534). 29650534
EML4-ALK ALK G1269A ALK I1171T Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK I1171T was identified as a compound mutation in transformed cells expressing ALK G1269A in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534). 29650534
EML4-ALK ALK L1196M ALK I1171S Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK I1171S 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 rearrange ALK I1171N ALK D1203N non-small cell lung carcinoma resistant Lorlatinib Clinical Study Actionable In a clinical study, an ALK-positive non-small cell lung cancer patient harboring ALK I1171N and D1203N in cis developed resistance to Lorlatinib (PF-06463922) after initial response (PMID: 29650534). 29650534
EML4-ALK ALK L1196M ALK F1174L 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
EML4-ALK ALK C1156Y ALK L1196M Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK L1196M was identified as a compound mutation in transformed cells expressing ALK C1156Y in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534). 29650534
EML4-ALK ALK C1156Y ALK I1171T Advanced Solid Tumor resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, ALK I1171T was identified as a compound mutation in transformed cells expressing ALK C1156Y in the context of EML4-ALK that acquired resistance to Lorlatinib (PF-06463922) in culture (PMID: 29650534). 29650534
ALK rearrange ALK C1156Y ALK L1198F non-small cell lung carcinoma resistant Lorlatinib Clinical Study Actionable In a clinical study, ALK D1203N was identified as an acquired mutation in an ALK-positive non-small cell lung cancer patient harboring ALK C1156Y who developed resistance to Lorlatinib (PF-06463922) after initial response (PMID: 29650534). 29650534