Reference Detail

Ref Type

Journal Article

PMID

(29636358)

Authors

McCoach CE, Le AT, Gowan K, Jones K, Schubert L, Doak A, Estrada-Bernal A, Davies KD, Merrick DT, Bunn PA, Purcell WT, Dziadziuszko R, Varella-Garcia M, Aisner DL, Camidge DR, Doebele RC

Title

Resistance Mechanisms to Targeted Therapies in ROS1+ and ALK+ Non-small Cell Lung Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	24	14	2018 Jul 15	3334-3347	Clin Cancer Res

URL

Abstract Text

Purpose: Despite initial benefit from tyrosine kinase inhibitors (TKIs), patients with advanced non-small cell lung cancer (NSCLC) harboring ALK (ALK+) and ROS1 (ROS1+) gene fusions ultimately progress. Here, we report on the potential resistance mechanisms in a series of patients with ALK+ and ROS1+ NSCLC progressing on different types and/or lines of ROS1/ALK-targeted therapy.Experimental Design: We used a combination of next-generation sequencing (NGS), multiplex mutation assay, direct DNA sequencing, RT-PCR, and FISH to identify fusion variants/partners and copy-number gain (CNG), kinase domain mutations (KDM), and copy-number variations (CNVs) in other cancer-related genes. We performed testing on 12 ROS1+ and 43 ALK+ patients.Results: One of 12 ROS1+ (8%) and 15 of 43 (35%) ALK + patients harbored KDM. In the ROS1+ cohort, we identified KIT and β-catenin mutations and HER2-mediated bypass signaling as non-ROS1-dominant resistance mechanisms. In the ALK+ cohort, we identified a novel NRG1 gene fusion, a RET fusion, 2 EGFR, and 3 KRAS mutations, as well as mutations in IDH1, RIT1, NOTCH, and NF1 In addition, we identified CNV in multiple proto-oncogenes genes including PDGFRA, KIT, KDR, GNAS, K/HRAS, RET, NTRK1, MAP2K1, and others.Conclusions: We identified a putative TKI resistance mechanism in six of 12 (50%) ROS1 + patients and 37 of 43 (86%) ALK+ patients. Our data suggest that a focus on KDMs will miss most resistance mechanisms; broader gene testing strategies and functional validation is warranted to devise new therapeutic strategies for drug resistance. Clin Cancer Res; 24(14); 3334-47. ©2018 AACR.

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Molecular Profile	Treatment Approach

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	L1198V	missense	unknown	ALK L1198V lies within the protein kinase domain of the Alk protein (UniProt.org). L1198V has been demonstrated to confer resistance to ALK inhibitors in the context of Alk fusions (PMID: 29636358, PMID: 35123209), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Nov 2023).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK HRAS amp	lung non-small cell carcinoma	predicted - resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical study, a non-small cell lung carcinoma patient harboring EML4-ALK treated with Xalkori (crizotinib) responded, but eventually progressed, and was subsequently found to harbor a presumed resistance alteration, HRAS amplification (PMID: 29636358).	29636358
ROS1 fusion ROS1 L1951R ROS1 L2026M	lung non-small cell carcinoma	predicted - resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical study, a non-small cell lung carcinoma patient harboring a ROS1 fusion progressed after 17 months of treatment with Xalkori (crizotinib), and was found to have acquired two additional mutations in trans, ROS1 L2026M and ROS1 L1951R, and cells derived from this patient showed partially decreased SHP2 and ERK1/2 signaling and ROS1 activation (PMID: 29636358).	29636358
EML4 - ALK FGFR1 amp	lung non-small cell carcinoma	predicted - resistant	Brigatinib	Case Reports/Case Series	Actionable	In a clinical study, a non-small cell lung carcinoma patient harboring EML4-ALK treated with Alunbrig (brigatinib) responded, but eventually progressed, and was subsequently found to harbor a presumed resistance alteration, FGFR1 amplification (PMID: 29636358).	29636358
EML4 - ALK ALK S1206C ALK E1210K	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 and ALK E1210K eventually progressed on treatment with Alunbrig (brigatinib) and was subsequently found to have acquired another resistance mutation, ALK S1206C in cis (PMID: 29636358).	29636358
EML4 - ALK ALK E1210K	lung non-small cell carcinoma	resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical study, a patient with non-small cell lung carcinoma harboring EML4-ALK progressed on treatment with Xalkori (crizotinib) and was subsequently found to harbor a secondary resistance mutation, ALK E1210K (PMID: 29636358).	29636358
ROS1 fusion KIT D816G	lung non-small cell carcinoma	predicted - resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical study, a non-small cell lung carcinoma patient harboring a ROS1 fusion developed resistance to treatment with Xalkori (crizotinib) and was subsequently found to have acquired KIT D816G (PMID: 29636358).	29636358
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
ROS1 fusion ROS1 L1951R ROS1 L2026M	lung non-small cell carcinoma	resistant	Ceritinib	Case Reports/Case Series	Actionable	In a clinical study, a non-small cell lung carcinoma patient co-harboring a ROS1 fusion, and two other mutations in trans, ROS1 L2026M, and ROS1 L1951R demonstrated resistance to treatment with Zykadia (ceritinib), and cells derived from this patient showed partially decreased SHP2 and ERK1/2 signaling and ROS1 activation (PMID: 29636358).	29636358