ALKoma: A Cancer Subtype with a Shared Target

Abstract

Anaplastic lymphoma kinase (ALK) is a receptor-type protein tyrosine kinase that is currently the focus of much attention in oncology. ALK is rendered oncogenic as a result of its fusion to NPM1 in anaplastic large cell lymphoma, to TPM3 or TPM4 in inflammatory myofibroblastic tumor, to EML4 in non–small cell lung carcinoma, and to VCL in renal medullary carcinoma. It is also activated as a result of missense mutations in neuroblastoma and anaplastic thyroid cancer. Whereas these various tumors arise in different organs, they share activated ALK, and a marked clinical efficacy with ALK inhibitors has already been shown for some of the tumors with ALK fusions. One of such compound, crizotinib, is now approved in the United States for the treatment of lung cancer positive for ALK rearrangement. I propose that tumors carrying abnormal ALK as an essential growth driver be collectively termed “ALKoma.” Significance: ALK acquires transforming ability through gene fusion or missense mutation in a wide range of human cancers. Some of these cancers, which I propose be collectively referred to as “ALKoma,” may all be effectively treated with small compounds or antibodies targeted to activated ALKs. Cancer Discov; 2(6); 495–502. © 2012 AACR.

Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target

“…Since the discovery of ALK as a gene target of the t(2;5) chromosomal translocation in anaplastic large cell lymphoma in 1994, ALK gene alterations, including gene fusions involving the ALK locus at 2p23, point mutations, and gene amplifications have been described in 18 different tumor types (8,9). The term "ALKoma" was suggested in order to unify these various tumor types arising in different organs but sharing ALK oncogenic activation as an essential tumor growth driver (24). Among epithelial tumors, ALK gene rearrangements are most common in lung carcinomas, varying from 4% to 7%, and rare in kidney, breast, colorectal, esophageal, thyroid, ovarian, and bladder carcinomas (8,9).…”

Genomically Driven Tumors and Actionability across Histologies:BRAF-Mutant Cancers as a Paradigm

“…The corollary to this question is whether or not the biomarker defines the tumor and represents a nosology in and of itself. Herein, we have used BRAFmutant cancers as one example in support of such a restructuring of cancer classification, but others have proposed a similar genetic-centric nosology such as ALKomas for tumors encompassing multiple organs but harboring aberrations in ALK that have either been shown to or are likely to respond to ALK inhibitors (92). While not clear-cut, increasingly the data show that the presence of certain genomic drivers, such as BRAF aberrations, predicts response to cognate inhibitors across multiple (though not all) tumor types.…”

Interrogation of individual intratumoral B lymphocytes from lung cancer patients for molecular target discovery

“…TPM4 is a member of the tropomyosin family of actin binding proteins. Anaplastic lymphoma kinase (ALK) is a receptor-type protein tyrosine kinase that is rendered oncogenic as a result of its fusion to TPM4 in inflammatory myofibroblastic tumor [35]. We investigated whether the antibody to TPM4 may have arisen due to the presence of such a fusion event by performing fluorescence in situ hybridization analysis on the tumor tissue that provided the B cells from which recombinant antibody T009 was cloned.…”