Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

Facchinetti, Francesco; Tiseo, Marcello; Maïo, Massimo Di; Graziano, Paolo; Bria, Emilio; Rossi, Giulio; Novello, Silvia

doi:10.21037/tlcr.2016.06.10

Cited by 40 publications

(29 citation statements)

References 115 publications

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“…Due to their ability to improve PFS and control brain metastases, these drugs are also frequently prescribed upfront. Third-generation ALK inhibitors including lorlatinib and ensartinib are currently investigated (8,9). Lorlatinib demonstrated clinical activity in resistant patients previously treated with two or more ALK inhibitors including second-generation inhibitors (10).…”

Section: Introductionmentioning

confidence: 99%

Acquired Resistance Mutations to ALK Inhibitors Identified by Single Circulating Tumor Cell Sequencing inALK-Rearranged Non–Small-Cell Lung Cancer

Pailler

Faugeroux

Oulhen

et al. 2019

Clinical Cancer Research

106

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Purpose: Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) inevitably develop resistance to ALK inhibitors. New diagnostic strategies are needed to assess resistance mechanisms and provide patients with the most effective therapy. We asked whether single circulating tumor cell (CTC) sequencing can inform on resistance mutations to ALK inhibitors and underlying tumor heterogeneity in ALK-rearranged NSCLC. Experimental Design: Resistance mutations were investigated in CTCs isolated at the single-cell level from patients at disease progression on crizotinib (n ¼ 14) or lorlatinib (n ¼ 3). Three strategies including filter laser-capture microdissection, fluorescence activated cell sorting, and the DEPArray were used. One hundred twenty-six CTC pools and 56 single CTCs were isolated and sequenced. Hotspot regions over 48 cancer-related genes and 14 ALK mutations were examined to identify ALK-independent and ALK-dependent resistance mechanisms. Results: Multiple mutations in various genes in ALKindependent pathways were predominantly identified in CTCs of crizotinib-resistant patients. The RTK-KRAS (EGFR, KRAS, BRAF genes) and TP53 pathways were recurrently mutated. In one lorlatinib-resistant patient, two single CTCs out of 12 harbored ALK compound mutations. CTC-1 harbored the ALK G1202R/F1174C compound mutation virtually similar to ALK G1202R/F1174L present in the corresponding tumor biopsy. CTC-10 harbored a second ALK G1202R/T1151M compound mutation not detected in the tumor biopsy. By copy-number analysis, CTC-1 and the tumor biopsy had similar profiles, whereas CTC-10 harbored multiple copynumber alterations and whole-genome duplication. Conclusions: Our results highlight the genetic heterogeneity and clinical utility of CTCs to identify therapeutic resistance mutations in ALK-rearranged patients. Single CTC sequencing may be a unique tool to assess heterogeneous resistance mechanisms and help clinicians for treatment personalization and resistance options to ALK-targeted therapies.

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Section: Introductionmentioning

confidence: 99%

Acquired Resistance Mutations to ALK Inhibitors Identified by Single Circulating Tumor Cell Sequencing inALK-Rearranged Non–Small-Cell Lung Cancer

Pailler

Faugeroux

Oulhen

et al. 2019

Clinical Cancer Research

106

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“…Anaplastic lymphoma kinase (ALK), known as ALK tyrosine kinase receptor or cluster of differentiation 246 (CD246), has been identified as one of the major oncogenes in tumor pathogenesis [8, 11, 12, 16, 21, 26, 51]. In NB, high expression levels of ALK closely correlates with poor outcomes, especially in high-risk NB [22, 42, 49].…”

Section: Introductionmentioning

confidence: 99%

The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model

Guan

Zhao

et al. 2017

Cancer Letters

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Activating germline mutations of anaplastic lymphoma kinase (ALK) occur in most cases of hereditary neuroblastoma (NB) and the constitutively active kinase activity of ALK promotes cell proliferation and survival in NB. Therefore, ALK kinase is a potential therapeutic target for NB. In this study, we show that the novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time. These results indicate that alectinib may be a promising therapeutic agent for the treatment of NB.

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“…(18,25) The EML4-ALK fusion oncoprotein requires an N-terminal coiled-coil domain of EML4 which is essential for dimerization of the fusion protein and constitutive activation of ALK kinase. (26) Tyrosine kinase inhibitors binding to an ATP-binding pocket of ALK, such as crizotinib, (27) ceritinib, (28)(29)(30)(31) and alectinib, (32,33) have been proven their clinical effectiveness for NSCLC with genetic alterations causing aberrant ALK activation. It was also reported that SUMOylation and glycosylation on the NPM-ALK rearranged oncoprotein affected the stability and phosphorylation of the fused protein in neuroblastoma.…”

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confidence: 99%

Effects of SMYD2‐mediated EML4‐ALK methylation on the signaling pathway and growth in non‐small‐cell lung cancer cells

et al. 2017

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A specific subtype of non‐small‐cell lung cancer (NSCLC) characterized with an EML4‐ALK fusion gene, which drives constitutive oncogenic activation of anaplastic lymphoma kinase (ALK), shows a good clinical response to ALK inhibitors. We have reported multiple examples implying the biological significance of methylation on non‐histone proteins including oncogenic kinases in human carcinogenesis. Through the process to search substrates for various methyltransferases using an in vitro methyltransferase assay, we found that a lysine methyltransferase, SET and MYND domain‐containing 2 (SMYD2), could methylate lysine residues 1451, 1455, and 1610 in ALK protein. Knockdown of SMYD2 as well as treatment with a SMYD2 inhibitor in two NSCLC cell lines with an EML4‐ALK gene significantly attenuated the phosphorylation levels of the EML4‐ALK protein. Substitutions of each of these three lysine residues to an alanine partially or almost completely diminished in vitro methylation of ALK. In addition, we found that exogenous introduction of EML4‐ALK protein with the substitution of lysine 1610 to an alanine in these two cell lines reduced the phosphorylation levels of AKT, one of the downstream oncogenic molecules in the EML4‐ALK pathway, and suppressed the growth of the two cell lines. We further showed that the combination of a SMYD2 inhibitor and an ALK inhibitor additively suppressed the growth of these two NSCLC cells, compared with single‐agent treatment. Our results shed light on a novel mechanism that modulates the kinase activity of the ALK fused gene product and imply that SMYD2‐mediated ALK methylation might be a promising target for development of a novel class of treatment for tumors with the ALK fused gene.

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Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

Cited by 40 publications

References 115 publications

Acquired Resistance Mutations to ALK Inhibitors Identified by Single Circulating Tumor Cell Sequencing inALK-Rearranged Non–Small-Cell Lung Cancer

Acquired Resistance Mutations to ALK Inhibitors Identified by Single Circulating Tumor Cell Sequencing inALK-Rearranged Non–Small-Cell Lung Cancer

The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model

Effects of SMYD2‐mediated EML4‐ALK methylation on the signaling pathway and growth in non‐small‐cell lung cancer cells

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