EML4-ALK positive lung cancer is a primary

malignant Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

lung tumor Lung tumors are neoplastic lung nodules. These include: Primary tumors of the lung/pulmonary system: * Bronchial leiomyoma, a rare, benign tumor * Lung cancer, the term commonly used to refer to ''carcinoma of the lung'' * Pulmonary carcinoid tu ...

whose

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...

s contain a characteristic abnormal configuration of DNA wherein the ''echinoderm microtubule-associated protein-like 4'' (''

EML4 Echinoderm microtubule-associated protein-like 4 is a protein that in humans is encoded by the ''EML4'' gene. This protein is involved in cancers when spliced with the anaplastic lymphoma kinase Anaplastic lymphoma kinase (ALK) also known as A ...

'')

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

is fused to the ''

anaplastic lymphoma kinase Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ''ALK'' gene. Identification Anaplastic lymphoma kinase (ALK) was originally d ...

'' (''ALK'')

. This abnormal gene fusion leads to the production of a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

( EML4-ALK) that appears, in many cases, to promote and maintain the malignant behavior of the

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

cells. The transforming ''EML4-ALK'' fusion gene was first reported in non-small cell lung carcinoma (NSCLC) in 2007.

Signs and symptoms

The signs and symptoms of this lung cancer variant seem to mimic those of the underlying major cell type.

Diagnosis

Classification

Most lung carcinomas containing the ''EML4-ALK'' gene fusion are

adenocarcinomas Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ) (AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or ...

. Some studies suggest that the papillary adenocarcinoma and the signet ring cell adenocarcinoma variants are more likely to carry this fused gene than other histological variants.

Screening

Screening for ALK positive lung cancer is now a standard of care in the United States and Canada. Screening can be done with immunostaining,

FISH Fish are aquatic, craniate, gill-bearing animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish as well as various extinct related groups. Approximately 95% of ...

, or next-generation sequencing (NGS).

Treatment

Crizotinib Crizotinib, sold under the brand name Xalkori among others, is an anti-cancer medication used for the treatment of non-small cell lung carcinoma (NSCLC). It acts as an ALK ( anaplastic lymphoma kinase) and ROS1 ( c-ros oncogene 1) inhibitor. ...

is a targeted therapy (FDA approved in 2011), manufactured by Pfizer and marketed under the brand name Xalkori and Crizalk that targets the EML4/ALK fusion gene. Ceritinib is a second generation targeted therapy (FDA approved in 2014), manufactured by Novartis and sold under the brand name Zykadia that also targets the EML4 fusion gene, but as a second generation drug it has a smaller molecule that allows superior penetration of the Blood Brain Barrier (BBB) over Crizotinib and is more capable of protecting the Central Nervous System (CNS).

Alectinib Alectinib (INN, marketed as Alecensa) is an oral drug that blocks the activity of anaplastic lymphoma kinase (ALK) and is used to treat non-small-cell lung cancer (NSCLC). It was developed by Chugai Pharmaceutical Co. Japan, which is part of th ...

another second generation targeted therapy and was approved (for this) by Japan in 2014Japan becomes first country to approve Roche’s alectinib for people with a specific form of advanced lung cancer
/ref> and by

US FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

in 2015.,New Oral Therapy To Treat ALK-Positive Lung Cancer. Dec 2015
/ref> manufactured by Genentech and marketed under the brand name Alecensa.

Brigatinib Brigatinib, sold under the brand name Alunbrig among others, is a small-molecule targeted cancer therapy being developed by Ariad Pharmaceuticals, Inc. Brigatinib acts as both an anaplastic lymphoma kinase (ALK) and epidermal growth factor re ...

a second generation targeted therapy (FDA approved in 2017), manufactured by Takeda and is marketed under the brand name Alunbrig. Ensartinib is a second generation targeted therapy (trial drug X-396), manufactured by XCovery.

Lorlatinib Lorlatinib, sold under the brand name Lorbrena in the United States, Canada, and Japan, and Lorviqua in the European Union, is an anti-cancer drug developed by Pfizer. It is an orally administered inhibitor of ALK and ROS1, two enzymes that play ...

is a third generation targeted therapy (FDA approved in 2018), manufactured by Pfizer.

Prognosis

Treatment with crizotinib achieves 60% response rate. However, crizotinib showed no improvement on overall survival compared to chemotherapy. This may be due to the fact that there was a 70% crossover rate to crizotinib in patients treated initially with chemotherapy. Also, patients who tested negative for EML4/ALK fusion had a response rate to crizotinib of up to 35%.

Epidemiology

''EML4-ALK'' gene fusions occur almost exclusively in carcinomas arising in non-smokers. About 4% of non-small-cell lung carcinomas involve an EML4-ALK tyrosine kinase fusion gene. 4–6% of lung adenocarcinomas involve the fusion gene. ''EML4-ALK'' mutation rarely occurs in combination with ''K-RAS'' or ''EGFR'' mutations.

References

{{Reflist, 2

External links

*Entrez Gen
EML4 echinoderm microtubule associated protein like 4 ''Homo sapiens''
Lung cancer