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Onco Targets Ther
2014 Mar 05;7:375-85. doi: 10.2147/OTT.S38868.
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Development of anaplastic lymphoma kinase (ALK) inhibitors and molecular diagnosis in ALK rearrangement-positive lung cancer.
Iwama E
,
Okamoto I
,
Harada T
,
Takayama K
,
Nakanishi Y
.
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The fusion of echinoderm microtubule-associated protein-like 4 with anaplastic lymphoma kinase (ALK) was identified as a transforming gene for lung cancer in 2007. This genetic rearrangement accounts for 2%-5% of non-small-cell lung cancer (NSCLC) cases, occurring predominantly in younger individuals with adenocarcinoma who are never- or light smokers. A small-molecule tyrosine-kinase inhibitor of ALK, crizotinib, was rapidly approved by the US Food and Drug Administration on the basis of its pronounced clinical activity in patients with ALK rearrangement-positive NSCLC. Next-generation ALK inhibitors, such as alectinib, LDK378, and AP26113, are also being developed in ongoing clinical trials. In addition, the improvement and validation of methods for the detection of ALK rearrangement in NSCLC patients will be key to the optimal clinical use of ALK inhibitors. We here summarize recent progress in the development of new ALK inhibitors and in the molecular diagnosis of ALK rearrangement-positive NSCLC.
Figure 1. Chemical structures and molecular weight (MW) of crizotinib, alectinib, LDK378, and AP26113.
Figure 2. Ongoing Phase III study (Profile 1014) of crizotinib for the treatment of ALK rearrangement-positive non-small-cell lung cancer.Abbreviations: ALK, anaplastic lymphoma kinase; FISH, fluorescence in situ hybridization; bid, twice daily; po, oral administration; PFS, progression-free survival.
Figure 3. Comparison of tyrosine-kinase inhibitor resistance mechanisms for ALK rearrangement-positive and EGFR mutation-positive non-small-cell lung cancer (NSCLC). Only 30% of cases of acquired crizotinib resistance in patients with ALK-rearranged NSCLC are attributable to various secondary mutations of ALK, with the remaining 70% of such cases being due to other mechanisms. In contrast, 60% of cases of acquired resistance to EGFR-tyrosine-kinase inhibitors in patients with EGFR mutation-positive NSCLC are caused by secondary mutation of EGFR, almost exclusively T790M, whereas only 40% of such cases are due to other resistance mechanisms.Abbreviations: ALK, anaplastic lymphoma kinase; EGFR, epidermal growth-factor receptor; SCLC, small-cell lung cancer.
Figure 4. Ongoing Phase III study (JapicCTI-132316) of alectinib for the treatment of ALK rearrangement-positive non-small-cell lung cancer.39Abbreviations: ALK, anaplastic lymphoma kinase; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; RT-PCR, reverse-transcription polymerase chain reaction; PFS, progression-free survival; bid, twice daily; po, oral administration.
Figure 5. Ongoing Phase III studies of LDK378 for the treatment of ALK rearrangement-positive non-small-cell lung cancer.Abbreviations: ALK, anaplastic lymphoma kinase; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; qd, once daily; po, oral administration; PFS, progression-free survival.
Figure 6. Schematic illustration for break-apart fluorescence in situ hybridization for detecting ALK rearrangements.Abbreviation: ALK, anaplastic lymphoma kinase.
Figure 7. Proposed algorithm for testing for ALK rearrangement in patients with non-small-cell lung cancer.Abbreviations: ALK, anaplastic lymphoma kinase; IHC, immunohistochemistry; RT-PCR, reverse-transcription polymerase chain reaction; FISH, fluorescence in situ hybridization.
Balak,
Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors.
2006, Pubmed
Balak,
Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors.
2006,
Pubmed
Camidge,
Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment.
2010,
Pubmed
Camidge,
Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.
2012,
Pubmed
Chihara,
More on crizotinib.
2011,
Pubmed
Choi,
Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer.
2008,
Pubmed
Choi,
EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.
2010,
Pubmed
,
Echinobase
Christensen,
Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma.
2007,
Pubmed
Doebele,
Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer.
2012,
Pubmed
Ferlay,
Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008.
2010,
Pubmed
Han,
Immunohistochemistry reliably detects ALK rearrangements in patients with advanced non-small-cell lung cancer.
2013,
Pubmed
Heuckmann,
ALK mutations conferring differential resistance to structurally diverse ALK inhibitors.
2011,
Pubmed
Katayama,
Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers.
2012,
Pubmed
Katayama,
Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK.
2011,
Pubmed
,
Echinobase
Koivunen,
EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer.
2008,
Pubmed
Kwak,
Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
2010,
Pubmed
Le Beau,
The t(2;5)(p23;q35): a recurring chromosomal abnormality in Ki-1-positive anaplastic large cell lymphoma.
1989,
Pubmed
Li,
ALK-rearranged lung cancer in Chinese: a comprehensive assessment of clinicopathology, IHC, FISH and RT-PCR.
2013,
Pubmed
Lynch,
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.
2004,
Pubmed
Maemondo,
Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.
2010,
Pubmed
Mano,
Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer.
2008,
Pubmed
,
Echinobase
Marsilje,
Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials.
2013,
Pubmed
Martelli,
EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues.
2009,
Pubmed
,
Echinobase
McDermott,
Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors.
2008,
Pubmed
Mino-Kenudson,
A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry.
2010,
Pubmed
Mitsudomi,
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial.
2010,
Pubmed
Morris,
Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.
1994,
Pubmed
Okamoto,
Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase-targeted therapy for advanced non-small cell lung cancer: molecular and clinical aspects.
2012,
Pubmed
,
Echinobase
Park,
Immunohistochemical screening for anaplastic lymphoma kinase (ALK) rearrangement in advanced non-small cell lung cancer patients.
2012,
Pubmed
Sakai,
A novel mass spectrometry-based assay for diagnosis of EML4-ALK-positive non-small cell lung cancer.
2012,
Pubmed
,
Echinobase
Sakamoto,
CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.
2011,
Pubmed
Sasaki,
The biology and treatment of EML4-ALK non-small cell lung cancer.
2010,
Pubmed
,
Echinobase
Sasaki,
A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors.
2011,
Pubmed
Selinger,
Testing for ALK rearrangement in lung adenocarcinoma: a multicenter comparison of immunohistochemistry and fluorescent in situ hybridization.
2013,
Pubmed
Sequist,
Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.
2011,
Pubmed
Seto,
CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study.
2013,
Pubmed
Shaw,
Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.
2009,
Pubmed
Shaw,
Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
2013,
Pubmed
Sholl,
Combined use of ALK immunohistochemistry and FISH for optimal detection of ALK-rearranged lung adenocarcinomas.
2013,
Pubmed
Soda,
Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
2007,
Pubmed
,
Echinobase
Soda,
A mouse model for EML4-ALK-positive lung cancer.
2008,
Pubmed
Sordella,
Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways.
2004,
Pubmed
Takeda,
Clinical outcome for EML4-ALK-positive patients with advanced non-small-cell lung cancer treated with first-line platinum-based chemotherapy.
2012,
Pubmed
Takeuchi,
KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer.
2009,
Pubmed
Takeuchi,
Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts.
2008,
Pubmed
Takezawa,
Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer.
2011,
Pubmed
Tamiya,
Severe acute interstitial lung disease after crizotinib therapy in a patient with EML4-ALK-positive non-small-cell lung cancer.
2013,
Pubmed
Tanizaki,
Activation of HER family signaling as a mechanism of acquired resistance to ALK inhibitors in EML4-ALK-positive non-small cell lung cancer.
2012,
Pubmed
To,
Detection of ALK rearrangement by immunohistochemistry in lung adenocarcinoma and the identification of a novel EML4-ALK variant.
2013,
Pubmed
,
Echinobase
Wallander,
Comparison of reverse transcription-polymerase chain reaction, immunohistochemistry, and fluorescence in situ hybridization methodologies for detection of echinoderm microtubule-associated proteinlike 4-anaplastic lymphoma kinase fusion-positive non-small cell lung carcinoma: implications for optimal clinical testing.
2012,
Pubmed
,
Echinobase
Wu,
Comparison of IHC, FISH and RT-PCR methods for detection of ALK rearrangements in 312 non-small cell lung cancer patients in Taiwan.
2013,
Pubmed
,
Echinobase
Yi,
Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score algorithm for FISH.
2011,
Pubmed
Ying,
Diagnostic value of a novel fully automated immunochemistry assay for detection of ALK rearrangement in primary lung adenocarcinoma.
2013,
Pubmed
Yu,
Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers.
2013,
Pubmed
Zhang,
Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen.
2011,
Pubmed
Zou,
An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms.
2007,
Pubmed
