Overview of Therapeutic Biomarkers in Cancer
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
Anaplastic lymphoma kinase (ALK) is abundantly expressed and oncogenic in cancers affecting children (anaplastic large cell lymphoma (ALCL) and neuroblastomas) and adults (most commonly non-small cell lung carcinomas (NSCLC) and rarely in other solid tumors), while it is absent from the majority of normal adult tissues. ROS1 is a receptor tyrosine kinase (encoded by the gene ROS1) with structural similarity to the ALK protein. The ALK fusion gene occurs in 3% to 5% of NSCLC, and incidence of ROS1 gene rearrangement is estimated at up to 2% of NSCLC [39, 40]. There are now three generations of inhibitors to these therapeutic targets. Crizotinib, a small-molecule inhibitor of the receptor tyrosine kinases c-Met and ALK, was approved for the treatment of patients with metastatic NSCLC whose tumors harbor ALK or ROS1 gene rearrangement (positivity) in 2011 (Chapter 16). Concurrently with the drug approval, FDA approved its companion diagnostic test—the Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.) [41, 42]. Ceritinib in 2014 and alectinib in 2015 were approved for the treatment of ALK-positive, metastatic NSCLC who have progressed or are intolerant to crizotinib. Additionally, a next-generation ALK/ROS1 tyrosine kinase inhibitor lorlatinib was approved as second-line or third-line therapy. It is a selective brain-penetrant ALK/ROS1 TKI active against the most known resistance mutations.
Small-Molecule Targeted Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
In healthy individuals the ALK (Anaplastic Lymphoma Kinase) protein is involved in the development and function of nervous system tissue. However, chromosomal translocations and fusions can give rise to an oncogenic form of ALK that has been implicated in the progression of non-small-cell lung carcinoma (NSCLC) and other cancer types. Approximately 4% of patients with NSCLC have a chromosomal rearrangement that generates a fusion gene between EML4 (Echinoderm Microtubule-Associated Protein-Like 4) and ALK, which results in constitutive kinase activity that contributes to carcinogenesis and drives the malignant phenotype. Researchers first identified the ALK fusion gene in 1994 as a chromosomal rearrangement in anaplastic large-cell lymphoma (ALCL). It is now known that 4–7% of NSCLC patients have EML4-ALK translocations, and genetic studies have confirmed that abnormal expression of ALK is a key driver in certain types of NSCLC, neuroblastomas, and ALCL. Interestingly, patients with this gene fusion are typically younger non-smokers who do not have mutations in either the EGFR or the K-RAS genes. Since ALK is not normally expressed significantly in normal adult tissues, it is a rational molecular target for cancer therapy.
Lung cancer
Pat Price, Karol Sikora in Treatment of Cancer, 2014
ALK is a member of the insulin receptor super-family of RTKs and is normally expressed only in the central nervous system in healthy adults, playing a role in neuronal cell differentiation. The ligand for ALK is not currently known, but binding leads to receptor dimerization and subsequent activation of a number of proliferative and pro-survival pathways such as mitogen-activated protein kinase (MAPK), PI3K and JAK-STAT. Somatic ALK fusions with EML4 in NSCLC were first described in 2007.23 Subsequently, other ALK fusion partners have been reported. The fusion protein has an activated ALK, leading to ligand-independent dimerization and constitutive activation. ALK fusion proteins have been identified in approximately 2%–7% of adenocarcinomas, predominantly of signet ring subtype. Clinically, these patients tend to be younger, are never-smokers, present with advanced disease and have a high incidence of brain metastases.
High grade gliomas in young children: The South Thames Neuro-Oncology unit experience and recent advances in molecular biology and targeted therapies
Published in Pediatric Hematology and Oncology, 2021
Janice Pearce, Komel Khabra, Henry Nanji, Joanna Stone, Karen Powell, Danielle Martin, Bassel Zebian, Samantha Hettige, Zita Reisz, Istvan Bodi, Safa Al-Sarraj, Leslie R. Bridges, Matthew Clarke, Chris Jones, Henry C. Mandeville, Sucheta Vaidya, Lynley V. Marshall, Fernando Carceller
The Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase involved in cell proliferation, progression and survival.35 Upregulation of ALK signaling can result from chromosomal translocations, activating mutations and gene amplifications.35 ALK has been found overexpressed in adult glioblastomas and ALK fusions have been reported in <1% pediatric HGG.36,37 ALK-fused tumors represent 41–47% of fusion-positive infant gliomas.4,5 ALK inhibitors have shown clinical activity in anecdotal reports of pediatric solid tumors and infant gliomas.4,38,39 Importantly, ALK-fused tumors seem to respond better to ALK inhibition than ALK-mutated tumors.40 Novel ALK inhibitors seem to display enhanced blood-brain barrier penetration.4,5 Overall, these findings make ALK inhibitors a very attractive strategy in ALK-fused infant gliomas.
Anaplastic lymphoma kinase inhibitors: an updated patent review (2014–2018)
Published in Expert Opinion on Therapeutic Patents, 2020
Yi-Min Liu, Chun-Nan Kuo, Jing-Ping Liou
ALK is a receptor tyrosine kinase involved in many types of cancers, particularly lymphoma and lung cancer. The development of ALK inhibitors accelerated dramatically after the first-generation ALK inhibitor was approved, but the resistance of ALK to treatment by ALK inhibitors is still an issue that must be solved. Not only can the three different mechanism, which mentioned in the text result in resistance, but also the bypass pathway and/or other mechanism-mediated resistance can lead to resistance. For example, cKIT gene amplification, cMET gene amplification, and epidermal growth factor receptor activation were found in crizotinib-, ceritinib-, or alectinib-resistant patients. To overcome this kind of resistance, targeting various targets is a theoretical strategy for further treatment. For instance, crizotinib also can target MET kinase. A phase I trial demonstrated that crizotinib had an antitumor effect in patients with NSCLC and MET amplification. The ORR was 40% and PFS was 6.7 months in patients with high MET amplification [97]. Although the number of patients with ALK or MET or other targets positive expression in the NSCLC population is small, ALK inhibitors offer goof treatment efficacy in the group with acceptable toxicity. There are still several small molecules in use as ALK inhibitors under clinical or preclinical development. Further studies are necessary to address the issue of overcoming ALK resistance.
Pharmacotherapeutic advances with anaplastic lymphoma kinase inhibitors for the treatment of non-small cell lung cancer
Published in Expert Opinion on Pharmacotherapy, 2020
Alice Indini, Erika Rijavec, Michele Ghidini, Claudia Bareggi, Donatella Gambini, Barbara Galassi, Paola Antonelli, Giulia Bettio, Clarissa Di Nubila, Francesco Grossi
ALK is a transmembrane receptor tyrosine kinase that activates multiple signaling pathways, such as PI3 K, AKT, JAK, STAT, MAPK and many others [4]. Gene rearrangements in the ALK domain are found in several types of cancers, suggesting that ALK reactivation plays a fundamental role in tumor development and progression [5]. ALK genetic alterations include point mutations, deletions and rearrangements; however the most common in NSCLC is translocation with the echinoderm microtubule-associated protein-like (EML-4), which belongs to the class of molecules inducing microtubule instability [6]. The formation of ALK fusion proteins results in activation and dysregulation of genes’ expression and signaling, which ultimately promote cell proliferation and survival [4]. In a minority of patients also ALK overexpression has been found; however, its oncogenic potential is not clear.
Related Knowledge Centers
- Chromosomal Translocation
- Dimerization
- Enzyme
- Fusion Protein
- Receptor Tyrosine Kinase
- Amino Acid
- Gene
- Anaplastic Large-Cell Lymphoma
- Kinase
- Npm1