Tyrosine kinases are involved in the pathogenesis of most cancers. However, few tyrosine kinases have been shown to have a well-defined pathogenetic role in lymphomas. The anaplastic lymphoma kinase (ALK) is the oncogene of most anaplastic large cell lymphomas (ALCL), driving transformation through many molecular mechanisms. In this Review, we will analyse how translocations or deregulated expression of ALK contribute to oncogenesis and how recent genetic or pharmacological tools, aimed at neutralizing its activity, can represent the basis for the design of powerful combination therapies.

The anaplastic lymphoma kinase in the pathogenesis of cancer.

The burgeoning field of anaplastic lymphoma kinase (ALK) in cancer encompasses many cancer types, from very rare cancers to the more prevalent non-small-cell lung cancer (NSCLC). The common activation of ALK has led to the use of the ALK tyrosine kinase inhibitor (TKI) crizotinib in a range of patient populations and to the rapid development of second-generation drugs targeting ALK. In this Review, we discuss our current understanding of ALK function in human cancer and the implications for tumour treatment.

Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology

Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK -rearranged malignancies, including non–small cell lung cancer. However, the clinical benefit of targeting ALK using tyrosine kinase inhibitors (TKI) is almost universally limited by the emergence of drug resistance. Diverse mechanisms of resistance to ALK TKIs have now been discovered, and these basic mechanisms are informing the development of novel therapeutic strategies to overcome resistance in the clinic. In this review, we summarize the current successes and challenges of targeting ALK. Significance: Effective long-term treatment of ALK -rearranged cancers requires a mechanistic understanding of resistance to ALK TKIs so that rational therapies can be selected to combat resistance. This review underscores the importance of serial biopsies in capturing the dynamic therapeutic vulnerabilities within a patient9s tumor and offers a perspective into the complexity of on-target and off-target ALK TKI resistance mechanisms. Therapeutic strategies that can successfully overcome, and potentially prevent, these resistance mechanisms will have the greatest impact on patient outcome. Cancer Discov; 7(2); 137–55. ©2017 AACR.

/pdf/targeting-alk-precision-medicine-takes-on-drug-resistance-yrm8clmerp.pdf

Targeting ALK: Precision Medicine Takes on Drug Resistance

RTKs (receptor tyrosine kinases) play important roles in cellular proliferation and differentiation. In addition, RTKs reveal oncogenic potential when their kinase activities are constitutively enhanced by point mutation, amplification or rearrangement of the corresponding genes. The ALK (anaplastic lymphoma kinase) RTK was originally identified as a member of the insulin receptor subfamily of RTKs that acquires transforming capability when truncated and fused to NPM (nucleophosmin) in the t(2;5) chromosomal rearrangement associated with ALCL (anaplastic large cell lymphoma). To date, many chromosomal rearrangements leading to enhanced ALK activity have been described and are implicated in a number of cancer types. Recent reports of the EML4 (echinoderm microtubule-associated protein like 4)-ALK oncoprotein in NSCLC (non-small cell lung cancer), together with the identification of activating point mutations in neuroblastoma, have highlighted ALK as a significant player and target for drug development in cancer. In the present review we address the role of ALK in development and disease and discuss implications for the future.

/pdf/anaplastic-lymphoma-kinase-signalling-in-development-and-433t6z17gl.pdf

Anaplastic lymphoma kinase: signalling in development and disease

The annexin superfamily consists of 13 calcium or calcium and phospholipid binding proteins with a significant degree of biological and structural homology (40–60%). First described in the late 1970s and subsequently referred to as macrocortin, renocortin, lipomodulin, lipocortin-1, and more recently Annexin 1, this 37 kDa calcium and phospholipid binding protein is a strong inhibitor of glucocorticoid-induced eicosanoid synthesis and PLA2. Recent interest in the biological activity of this intriguing molecule has unraveled important functional attributes of Annexin 1 in a variety of inflammatory pathways, on cell proliferation machinery, in the regulation of cell death signaling, in phagocytic clearance of apoptosing cells, and most importantly in the process of carcinogenesis. Here we attempt to present a short review on these diverse biological activities of an interesting and important molecule, which could be a potential target for novel therapeutic intervention in a host of disease states.— Lim, L. ...

Annexin 1: the new face of an old molecule

Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer death in China. In the present study, proteins in tumors and adjacent normal esophageal tissues from 41 patients with ESCC were extracted, and two-dimensional electrophoresis (2-DE) was performed using the pH 3-10 and 4-7 immobilized pH gradient strips. The protein spots expressed differentially between tumors and normal tissues were identified by matrix-assisted laser desorption/ionization and liquid chromatography electrospray/ionization ion trap mass spectrometry. A total of 22 proteins differentially expressed between ESCC and normal esophageal tissues were identified, in which 17 proteins were upregulated and 5 downregulated in tumors. Biological functions of these proteins are related to cell signal transduction, cell proliferation, cell motility, glycolysis, regulation of transcription, oxidative stress processes, and protein folding. Some of the proteins obtained were confirmed by Western blotting and immunohistochemical staining. We showed that high expression of calreticulin and 78-kDa glucose-regulated protein (GRP78) were correlated with poor prognosis by Kaplan-Meier analysis and log rank analysis. Zinc finger protein 410, annexin V, similar to the ubiquitin-conjugating enzyme E2 variant 1 isoform c, mutant hemoglobin beta chain, TPM4-ALK fusion oncoprotein type 2, similar to heat shock congnate 71-kDa protein, GRP78, and pyruvate kinase M2 (M2-PK) were for the first time observed to be dysregulated in human ESCC tissues. The proteins here identified will contribute to the understanding of the tumorigenesis and progression of Chinese ESCC and may potentially provide useful markers for diagnosis or targets for therapeutic intervention and drug development.

Proteomic profiling of proteins dysregulted in Chinese esophageal squamous cell carcinoma

The development and progression of human cancer are believed to be due to the alterations of multiple genes or/and their protein products. For identifying the proteins associated with esophageal cancer, we analysed the protein profiles of 24 pairs of esophageal squamous cell carcinomas/matched adjacent normal epithelia. Microdissection of routinely unstained frozen sections was performed to purify cancerous and epithelial cells. The protein expression profiles were obtained by two-dimensional electrophoresis. Selected proteins dysregulated in tumors were identified by MALDI-TOF-MS. Three isoforms of annexin I were detected in normal esophageal mucosa and down-regulated in esophageal squamous cell carcinomas. RT-PCR analysis showed annexin I mRNA levels were significantly reduced in 17 out of 24 carcinomas. Immunohistochemistry demonstrated that annexin I appeared strong positive in all normal epithelia layers except basal cells. In cancer tissues, decreased expression of annexin I was observed in 12 out of 16 well differentiated tumors, 16 out of 17 moderately differentiated tumors, and 3 out of 3 poorly differentiated tumors as compared with the corresponding normal esophageal epithelia. There was a significant correlation between annexin I expression and the status of tumor differentiation. Well differentiated tumors presented stronger immunohistochemical reaction than moderately and poorly differentiated tumors. These data suggested that there existed three different isoforms of annexin I in normal esophageal epithelia, which may be the results of post-translational modification. Down-expression of three annexin I isoforms was a frequent event in esophageal carcinogenesis.

Three isoforms of annexin I are preferentially expressed in normal esophageal epithelia but down-regulated in esophageal squamous cell carcinomas

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Proteomic profiling of proteins dysregulted in Chinese esophageal squamous cell carcinoma

Three isoforms of annexin I are preferentially expressed in normal esophageal epithelia but down-regulated in esophageal squamous cell carcinomas