Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
Target Oncol
2013 Mar 01;81:55-67. doi: 10.1007/s11523-012-0250-9.
Show Gene links
Show Anatomy links
ALK inhibitors: a new targeted therapy in the treatment of advanced NSCLC.
Casaluce F
,
Sgambato A
,
Maione P
,
Rossi A
,
Ferrara C
,
Napolitano A
,
Palazzolo G
,
Ciardiello F
,
Gridelli C
.
???displayArticle.abstract???
The anaplastic lymphoma kinase (ALK) fusion gene is a key oncogenic driver in a subset of patients with advanced non-small cell lung cancer (NSCLC). Oncogenic fusion genes, including echinoderm microtubule-associated protein-like 4 (EML4) and ALK, have been detected in approximately 2-7 % of NSCLC patients. Fluorescence in situ hybridization (FISH) is the recommended method for detecting ALK gene rearrangement. EML4-ALK fusion genes define a molecular subset of NSCLC with distinct clinical characteristic (lung adenocarcinoma, never or former smoker, usually mutually exclusive with EGFR mutations). Crizotinib (PF-02341066) is an orally bioavailable, ATP-competitive, small molecule inhibitor of both the receptor tyrosine kinases ALK and c-MET (hepatocyte growth factor receptor). Crizotinib has been shown to yield important clinical benefit such as objective response rate, progression-free survival (PFS), and anticipated improvements in quality of life when used in pretreated patients with advanced NSCLC harboring EML4-ALK gene rearrangement. Preliminary phase II data suggested that crizotinib is safe and well tolerated with rapid and robust antitumor activity. A phase III randomized trial in a second-line setting showed response rate and PFS (primary study endpoint) advantage for crizotinib as compared to second-line chemotherapy. Treatment-related adverse events, predominantly restricted to the gastrointestinal and visual systems, are generally self-limiting or easily managed. Crizotinib is a new standard of care for patients with advanced, ALK-positive, NSCLC. In this review, we will discuss the discovery of ALK rearrangements, the clinical epidemiology of lung cancer driven by ALK, the clinical data for ALK-targeted therapy in NSCLC, and ongoing ALK inhibitor-based clinical trials.
Amin,
Pathobiology of ALK+ anaplastic large-cell lymphoma.
2007, Pubmed
Amin,
Pathobiology of ALK+ anaplastic large-cell lymphoma.
2007,
Pubmed
Bang,
The potential for crizotinib in non-small cell lung cancer: a perspective review.
2011,
Pubmed
,
Echinobase
Bergethon,
ROS1 rearrangements define a unique molecular class of lung cancers.
2012,
Pubmed
Boland,
Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up-regulation in non-small cell lung carcinomas.
2009,
Pubmed
Camidge,
Treating ALK-positive lung cancer--early successes and future challenges.
2012,
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
Camidge,
Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed.
2011,
Pubmed
Camidge,
Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment.
2010,
Pubmed
Chen,
Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene.
2010,
Pubmed
Cheng,
CEP-28122, a highly potent and selective orally active inhibitor of anaplastic lymphoma kinase with antitumor activity in experimental models of human cancers.
2012,
Pubmed
Chiarle,
The anaplastic lymphoma kinase in the pathogenesis of cancer.
2008,
Pubmed
Choi,
EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.
2010,
Pubmed
,
Echinobase
Choi,
Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer.
2008,
Pubmed
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
Fancelli,
1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile.
2006,
Pubmed
Ferlay,
Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008.
2010,
Pubmed
Galkin,
Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK.
2007,
Pubmed
Hernández,
TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations.
1999,
Pubmed
Horn,
EML4-ALK: honing in on a new target in non-small-cell lung cancer.
2009,
Pubmed
Houtman,
Echinoderm microtubule-associated protein like protein 4, a member of the echinoderm microtubule-associated protein family, stabilizes microtubules.
2007,
Pubmed
,
Echinobase
Inamura,
EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset.
2009,
Pubmed
,
Echinobase
Inamura,
EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers.
2008,
Pubmed
,
Echinobase
Jake Slavish,
Design and synthesis of a novel tyrosine kinase inhibitor template.
2009,
Pubmed
Jokoji,
Combination of morphological feature analysis and immunohistochemistry is useful for screening of EML4-ALK-positive lung adenocarcinoma.
2010,
Pubmed
,
Echinobase
Katayama,
Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK.
2011,
Pubmed
,
Echinobase
Katayama,
Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers.
2012,
Pubmed
Koivunen,
EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer.
2008,
Pubmed
Kruczynski,
Antitumor activity of pyridoisoquinoline derivatives F91873 and F91874, novel multikinase inhibitors with activity against the anaplastic lymphoma kinase.
2009,
Pubmed
Kwak,
Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
2010,
Pubmed
Li,
Development of anaplastic lymphoma kinase (ALK) small-molecule inhibitors for cancer therapy.
2008,
Pubmed
Lovly,
Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors.
2011,
Pubmed
Lynch,
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.
2004,
Pubmed
Martelli,
EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues.
2009,
Pubmed
,
Echinobase
Milkiewicz,
Synthesis and structure-activity relationships of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazines as potent and selective inhibitors of the anaplastic lymphoma kinase.
2010,
Pubmed
Mok,
Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.
2009,
Pubmed
Morris,
Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.
1994,
Pubmed
Okamoto,
Virtual screening and further development of novel ALK inhibitors.
2011,
Pubmed
Paez,
EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.
2004,
Pubmed
Park,
Immunohistochemical screening for anaplastic lymphoma kinase (ALK) rearrangement in advanced non-small cell lung cancer patients.
2012,
Pubmed
Perner,
EML4-ALK fusion lung cancer: a rare acquired event.
2008,
Pubmed
Pollmann,
Human EML4, a novel member of the EMAP family, is essential for microtubule formation.
2006,
Pubmed
Rikova,
Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.
2007,
Pubmed
Rodig,
Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population.
2009,
Pubmed
Rosell,
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
2012,
Pubmed
Sabbatini,
GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers.
2009,
Pubmed
Sakairi,
EML4-ALK fusion gene assessment using metastatic lymph node samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration.
2010,
Pubmed
,
Echinobase
Sakamoto,
CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.
2011,
Pubmed
Sandler,
Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.
2006,
Pubmed
Sasaki,
The biology and treatment of EML4-ALK non-small cell lung cancer.
2010,
Pubmed
,
Echinobase
Schiller,
Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
2002,
Pubmed
Sequist,
Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer.
2010,
Pubmed
Shaw,
Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.
2009,
Pubmed
Shaw,
Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.
2011,
Pubmed
Shinmura,
EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas.
2008,
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
Takahashi,
Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene.
2010,
Pubmed
,
Echinobase
Takeda,
Successful long-term treatment with pemetrexed of NSCLC associated with EML4-ALK and low thymidylate synthase expression.
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,
Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer.
2011,
Pubmed
Wasik,
Anaplastic lymphoma kinase (ALK)-induced malignancies: novel mechanisms of cell transformation and potential therapeutic approaches.
2009,
Pubmed
Weickhardt,
Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer.
2012,
Pubmed
Wong,
The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS.
2009,
Pubmed
,
Echinobase
Yasuda,
Bronchoscopic microsampling is a useful complementary diagnostic tool for detecting lung cancer.
2011,
Pubmed
Zhang,
Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen.
2011,
Pubmed
Zhang,
Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression.
2010,
Pubmed
Zou,
An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms.
2007,
Pubmed
