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Ref Type Journal Article
PMID (27432227)
Authors Gainor JF, Dardaei L, Yoda S, Friboulet L, Leshchiner I, Katayama R, Dagogo-Jack I, Gadgeel S, Schultz K, Singh M, Chin E, Parks M, Lee D, DiCecca RH, Lockerman E, Huynh T, Logan J, Ritterhouse LL, Le LP, Muniappan A, Digumarthy S, Channick C, Keyes C, Getz G, Dias-Santagata D, Heist RS, Lennerz J, Sequist LV, Benes CH, Iafrate AJ, Mino-Kenudson M, Engelman JA, Shaw AT
Title Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 6 10 2016 10 1118-1133 Cancer Discov
URL
Abstract Text Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALKG1202R, increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib. These findings highlight the importance of repeat biopsies and genotyping following disease progression on targeted therapies, particularly second-generation ALK inhibitors. Cancer Discov; 6(10); 1118-33. ©2016 AACRSee related commentary by Qiao and Lovly, p. 1084This article is highlighted in the In This Issue feature, p. 1069.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
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 D1203N missense unknown ALK D1203N lies within the protein kinase domain of the Alk protein (UniProt.org). D1203N has been demonstrated to occur as a secondary drug resistance mutation in the context of ALK fusions (PMID: 35123209, PMID: 27432227, PMID: 28434515), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Aug 2024). Y
ALK E1210K missense unknown ALK E1210K lies within the protein kinase domain of the Alk protein (UniProt.org). E1210K has been demonstrated to occur as a secondary drug resistance mutation in the context of ALK fusions (PMID: 29650534, PMID: 35123209, PMID: 27432227), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Aug 2024). Y
ALK G1202del deletion unknown ALK G1202del results in the deletion of an amino acid in the protein kinase domain of the Alk protein at amino acid 1202 (UniProt.org). G1202del has been demonstrated to occur as a secondary drug resistance mutation in the context of EML4-ALK (PMID: 27432227), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Aug 2024). Y
ALK V1180L missense unknown ALK V1180L lies within the protein kinase domain of the Alk protein (UniProt.org). V1180L has been demonstrated to occur as a secondary resistance mutation in the context of EML4-ALK (PMID: 25228534, PMID: 27432227, PMID: 35324529), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Aug 2024). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK L1198F Advanced Solid Tumor conflicting Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK L1198F demonstrated sensitivity to Alecensa (alectinib) treatment in culture (PMID: 27432227). 27432227
EML4 - ALK ALK G1202del Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK G1202del demonstrated sensitivity to treatment with Lorlatinib (PF-06463922) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK F1174C ALK D1203N Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK F1174C did not response to treatment with Alecensa (alectinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK F1174C Advanced Solid Tumor conflicting Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK F1174C were sensitive to treatment with Zykadia (ceritinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK D1203N ALK E1210K Advanced Solid Tumor decreased response Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK E1210K demonstrated a decreased response to treatment with Zykadia (ceritinib) compared to cells expressing EML4-ALK in culture (PMID: 27432227). 27432227
ALK rearrange ALK amp lung non-small cell carcinoma resistant Crizotinib Case Reports/Case Series Actionable In a clinical study, three patients with non-small cell lung carcinoma co-harboring an ALK rearrangement and ALK amplification demonstrated resistance to Xalkori (crizotinib) treatment (PMID: 27432227). 27432227
EML4 - ALK ALK I1171N Advanced Solid Tumor predicted - resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK I1171N demonstrated a decreased response to treatment with Xalkori (crizotinib) compared to cells expressing EML4-ALK in culture (PMID: 27432227). 27432227
EML4 - ALK ALK F1174C ALK D1203N Advanced Solid Tumor decreased response Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK F1174C demonstrated a decreased response to treatment with Alunbrig (brigatinib) when compared to cells expressing EML4-ALK in culture (PMID: 27432227). 27432227
EML4 - ALK ALK I1171T Advanced Solid Tumor predicted - resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK I1171T demonstrated a decreased response to treatment with Xalkori (crizotinib) compared to cells expressing EML4-ALK in culture (PMID: 27432227). 27432227
EML4 - ALK ALK E1210K Advanced Solid Tumor sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK E1210K demonstrated sensitivity to treatment with Zykadia (ceritinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK D1203N Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK D1203N demonstrated sensitivity to treatment with Lorbrena (lorlatinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK D1203N Advanced Solid Tumor sensitive Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK D1203N demonstrated sensitivity to treatment with Alecensa (alectinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK I1171N Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK I1171N demonstrated resistance to treatment with Alecensa (alectinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK L1196M Advanced Solid Tumor conflicting Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK L1196M demonstrated sensitivity to Lorbrena (lorlatinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK L1196M Advanced Solid Tumor sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK L1196M demonstrated sensitivity to treatment with Zykadia (ceritinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK G1202del Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK G1202del demonstrated moderate resistance to treatment with Alecensa (alectinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK D1203N Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK D1203N demonstrated sensitivity to treatment with Alunbrig (brigatinib) in culture (PMID: 27432227). 27432227
ALK rearrange ALK E1210K lung non-small cell carcinoma predicted - resistant Crizotinib Case Reports/Case Series Actionable In a clinical case study, a patient with ALK-rearranged non-small cell lung cancer demonstrated disease progression when treated with Xalkori (crizotinib) due to a secondary acquired resistance mutation, ALK E1210K (PMID: 27432227). 27432227
EML4 - ALK ALK G1202del Advanced Solid Tumor decreased response Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK G1202del demonstrated a decreased response to treatment with Zykadia (ceritinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK I1171N Advanced Solid Tumor sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK I1171N demonstrated sensitivity to treatment with Zykadia (ceritinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK F1174C ALK D1203N Advanced Solid Tumor resistant Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK F1174C demonstrated resistance to treatment with Zykadia (ceritinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK G1202del Advanced Solid Tumor decreased response Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK G1202del demonstrated a decreased response to treatment with Xalkori (crizotinib) compared to cells expressing EML4-ALK in culture (PMID: 27432227). 27432227
EML4 - ALK ALK I1171N Advanced Solid Tumor conflicting Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK I1171N demonstrated sensitivity to treatment with Lorbrena (lorlatinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK D1203N ALK E1210K Advanced Solid Tumor decreased response Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK E1210K demonstrated a decreased response to treatment with Xalkori (crizotinib) compared to cells expressing EML4-ALK in culture (PMID: 27432227). 27432227
EML4 - ALK ALK G1202R Advanced Solid Tumor conflicting Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK G1202R demonstrated sensitivity to treatment with Lorbrena (lorlatinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK D1203N Advanced Solid Tumor sensitive Ceritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK D1203N demonstrated sensitivity to treatment with Zykadia (ceritinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK E1210K Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK E1210K demonstrated sensitivity to treatment with Alunbrig (brigatinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK E1210K Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK E1210K demonstrated sensitivity to treatment with Lorlatinib (PF-06463922) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK F1174C Advanced Solid Tumor conflicting Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK with ALK F1174C demonstrated sensitivity to Alecensa (alectinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK D1203N ALK E1210K Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK E1210K demonstrated sensitivity to treatment with Lorlatinib (PF-06463922) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK D1203N Advanced Solid Tumor predicted - resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK D1203N demonstrated a decreased response to treatment with Xalkori (crizotinib) compared to cells expressing EML4-ALK in culture (PMID: 27432227). 27432227
EML4 - ALK ALK I1171N Advanced Solid Tumor sensitive Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK I1171N demonstrated sensitivity to treatment with Alunbrig (brigatinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK D1203N ALK E1210K Advanced Solid Tumor decreased response Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK E1210K demonstrated a decreased response to treatment with Alunbrig (brigatinib) when compared to cells expressing EML4-ALK in culture (PMID: 27432227). 27432227
EML4 - ALK ALK E1210K Advanced Solid Tumor conflicting Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK E1210K demonstrated sensitivity to treatment with Alecensa (alectinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK I1171S Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK I1171S demonstrated sensitivity to treatment with Lorbrena (lorlatinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK F1174C ALK D1203N Advanced Solid Tumor resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK F1174C demonstrated resistance to treatment with Xalkori (crizotinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK D1203N ALK E1210K Advanced Solid Tumor resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK E1210K did not response to treatment with Alecensa (alectinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK I1171T Advanced Solid Tumor conflicting Alectinib Preclinical - Cell culture Actionable In a preclinical study, a transformed cell line expressing EML4-ALK with ALK I1171T demonstrated sensitivity to Alecensa (alectinib) treatment in culture (PMID: 27432227). 27432227
EML4 - ALK ALK I1171T Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK I1171T demonstrated sensitivity to treatment with Lorbrena (lorlatinib) in culture (PMID: 27432227). 27432227
EML4 - ALK ALK I1171S Advanced Solid Tumor conflicting Brigatinib Preclinical - Cell culture Actionable In a preclinical study, Alunbrig (brigatinib) inhibited growth of transformed cells expressing EML4-ALK with ALK I1171S in culture (PMID: 27432227). 27432227
EML4 - ALK ALK G1202del Advanced Solid Tumor decreased response Brigatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing EML4-ALK and ALK G1202del demonstrated a decreased response to treatment with Alunbrig (brigatinib) compared to cells expressing EML4-ALK in culture (PMID: 27432227). 27432227
EML4 - ALK ALK F1174C ALK D1203N Advanced Solid Tumor decreased response Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EML4-ALK, ALK D1203N, and ALK F1174C demonstrated a decreased response to treatment with Lorlatinib (PF-06463922) in culture compared to cells expressing wild-type EML4-ALK (PMID: 27432227). 27432227
EML4 - ALK ALK I1171S Advanced Solid Tumor conflicting Ceritinib Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited growth of transformed cells expressing EML4-ALK with ALK I1171S in culture (PMID: 27432227). 27432227