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The ALK gene encodes a transmembrane tyrosine kinase receptor. ALK is physiologically expressed in the nervous system during embryogenesis, but its expression decreases postnatally. ALK first emerged in the field of oncology in 1994 when it was identified to fuse to NPM1 in anaplastic large‐cell lymphoma. Since then, ALK has been associated with other types of cancers, including non‐small‐cell lung cancer (NSCLC). More than 19 different ALK fusion partners have been discovered in NSCLC, including EML4, KIF5B, KLC1, and TPR. Most of these ALK fusions in NSCLC patients respond well to the ALK inhibitor, crizotinib. In this paper, we reviewed fusion partner genes with ALK, detection methods for ALK‐rearrangement (ALK‐R), and the ALK‐tyrosine kinase inhibitor, crizotinib, used in NSCLC patients.

Anaplastic lymphoma kinase (ALK) fusion is a well‐defined biomarker for ALK tyrosine kinase inhibitors (TKIs) treatment in non‐small cell lung cancer (NSCLC). Alectinib, a second‐generation ALK‐TKI, has been shown to have significantly longer progression‐free survival (PFS) than first‐generation ALK inhibitors in untreated ALK‐rearranged NSCLC patients. However, its clinical efficacy on rare ALK fusions remains unclear. Herein, two advanced NSCLC patients received first‐line alectinib treatment, given their positive ALK fusion status as determined by immunohistochemistry (IHC) testing results. Patients showed limited clinical response (PFS: 4 months) and primary resistance to alectinib respectively. Molecular profiling using next‐generation sequencing (NGS) further revealed a striatin (STRN)‐ALK fusion in the first patient accompanied by MET amplification, and a LIM domain only protein 7 (LMO7)‐ALK fusion in another patient without any other known oncogenic alterations. Both patients demonstrated improved survival after they switched to second‐line crizotinib (PFS: 11 months) and ensartinib (PFS: 18 months), respectively, up till the last follow‐up assessment. In conclusion, the clinical efficacy of ALK‐TKIs including alectinib for lung cancer with uncommon ALK gene fusions is still under evaluation. This study and literature review results showed mixed responses to alectinib in NSCLC patients who harboured rare ALK fusions. Comprehensive molecular profiling of tumour is thus strongly warranted for precise treatment strategies.

Anaplastic lymphoma kinase (ALK), a tyrosine kinase receptor of the RTK insulin superfamily, was named after its initial identification in anaplastic large cell lymphoma (ALCL). Following a reciprocal chromosomal translocation with nucleophosmin 1 (NPM1), ALK protein is abnormally expressed, promoting the malignant transformation of T cells into a more aggressive lymphoma. The inhibition of ALK activity could therefore benefit ALK+ ALCL patients. Despite the market availability and success of ALK tyrosine kinase inhibitors (TKIs), real‐world ALK+ ALCL patients exhibit significant heterogeneity in terms of disease stage at first diagnosis, tumor progression, and responses to medication. This indicates a need for more detailed differentiation of ALK+ ALCL patients in clinical practice. Here, we discovered that apurinic/apyrimidinic endonuclease‐reduction/oxidation factor 1 (APE1/REF1), an interacting partner of NPM1, could stabilize NPM1‐ALK fusion protein oligomers and enhance ALK tumor‐promoting activity and growth, decreasing cell sensitivity to ALK‐TKIs. Our results also reveal that disruption of the interaction weakens cell growth and augments the therapeutic efficacy of crizotinib and alectinib, ALK‐TKIs, against ALK+ ALCL. Thus, high expression of APE1 indicates a faster growth of ALK+ ALCL; targeting this interaction may potentially achieve improved therapeutic outcomes, providing a reference for more precise treatment of ALK+ ALCL patients in clinical practice. The multifunctional DNA repair protein APE1 could activate NPM1‐ALK and reduce ALK‐TKI sensitivity through stabilization of NPM1‐ALK oligomer. APE1 low expression or mutation of the interaction point decreased tumor growth and increased TKI sensitivity in NPM1‐ALK+ ALCL.

Anaplastic lymphoma kinase (ALK) rearrangement is identified in 3–7% of advanced non-small cell lung cancer (NSCLC) cases, and ALK tyrosine kinase inhibitors (TKIs) have revolutionized the management of this subset of NSCLC patients. ALK–TKIs have been proven highly effective in ALK-rearranged advanced NSCLC patients, but after initial responses and benefit, a subsequent progression inevitably occurs. Understanding acquired-resistance mechanisms and defining an appropriate algorithm is becoming even more essential, particularly considering the availability of extremely efficacious next-generation ALK inhibitors. The aim of this review is the analysis of current data about ALK inhibition as a therapeutic strategy in ALK-rearranged NSCLC management, with a focus on a specific ALK–TKI, alectinib. Alectinib is a highly selective inhibitor of ALK and showed systemic and central nervous system (CNS) efficacy in the treatment of this particular population. The change of first-line approach, and consequently of further lines of therapy, in ALK-rearranged NSCLC patients is still a matter of debate. A summary of evidence from randomized trials evaluating alectinib will be presented in order to discuss the available clinical evidence, safety and place in therapy.

Patients harboring rearrangements of anaplastic lymphoma kinase (ALK) fusion may respond differently to ALK tyrosine kinase inhibitors (TKIs) depending on changes in the type of ALK rearrangements. We report the first documented case of KANK1‐ALK fusion in mucinous lung adenocarcinoma, co‐occurring with TP53 mutation. The patient underwent targeted therapy with loratinib and iruplinalkib, followed by alternative chemotherapy. Unfortunately, the KANK1‐ALK fusion in this patient exhibited resistance to all the existing ALK‐TKIs, and the patient's condition has worsened repeatedly. Uncommon ALK fusion patterns present substantial therapeutic obstacles in clinical practice. Accurate detection of ALK fusion types is of great significance in formulating precise treatment plans. An increasing number of clinical specimens have detected rare fusions, and the treatment of rare fusions may be a research direction in the future.

Lung cancer is the most malignant tumor in the worldwide. About 3%‐5% non‐small cell lung cancer (NSCLC) patients carry anaplastic lymphoma kinase (ALK) gene fusions and receive great benefits from ALK‐targeted therapy. However, drug resistance inevitably occurs even with the most potent inhibitor drug lorlatinib. About half of the resistance are caused by alteration in ALK proteins for earlier ALK TKI drugs and near one‐third of loratinib resistant cases are caused by compound mutations without current effective treatment strategy in clinic. Novel strategies are in great need to overcome drug resistance. Lately, two novel strategies have been developed and attracted great attentions for their potentials to overcome drug resistance problems: (1) developed small compact macrocyclic ALK kinase inhibitors and (2) developed ALK targeted proteolysis‐targeting chimera (PROTAC) drugs. The macrocyclic molecules are small and compact in size, brain barrier permeable, and highly potent against lorlatinib‐resistant compound mutations. Developed ALK targeted PROTAC molecules could degrade oncogenic ALK driver proteins. Some showed superiority in killing ALK positive cancer cells and inhibiting the growth of cells expressing G1202R resistant ALK proteins comparing to inhibitor drugs. The update on these two treatment strategies was reviewed. Acquired resistance mutations including G1202R and L1196M, alone or in compound form, in ALK proteins lead to drug resistance to ALK‐targeted therapy. Two novel strategies showed great potential in overcoming such resistance: (1) More effective inhibition by small and compact macrocyclic inhibitors; (2) Degradation of oncogenic ALK proteins including those with resistant mutations by ALK targeted proteolysis‐targeting chimeras.

The anaplastic lymphoma kinase (ALK) receptor is a membrane-bound tyrosine kinase. The pathogenesis of several cancers is closely related to aberrant forms of ALK or aberrant ALK expression, including ALK fusion proteins, ALK-activated point mutations, and ALK amplification. Clinical applications of different ALK inhibitors represent significant progress in targeted therapy. Knowledge of different aspects of ALK biology can provide significant information to further the understanding of this receptor tyrosine kinase. In this mini-review, we briefly summarize different features of ALK. We also summarize some recent research advances on ALK fusion proteins in cancers.

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase involved in neuronal and gut development. Initially discovered in T cell lymphoma, ALK is frequently affected in diverse cancers by oncogenic translocations. These translocations involve different fusion partners that facilitate multimerisation and autophosphorylation of ALK, resulting in a constitutively active tyrosine kinase with oncogenic potential. ALK fusion proteins are involved in diverse cellular signalling pathways, such as Ras/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt and Janus protein tyrosine kinase (JAK)/STAT. Furthermore, ALK is implicated in epigenetic regulation, including DNA methylation and miRNA expression, and an interaction with nuclear proteins has been described. Through these mechanisms, ALK fusion proteins enable a transcriptional programme that drives the pathogenesis of a range of ALK-related malignancies.

Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along with possible therapeutic strategies that may overcome the development of resistance.

Abstract ALK-rearranged renal cell carcinoma (ALK-RCC) is a very rare novel molecularly defined entity in the recently published fifth edition of the World Health Organization classification of tumours. We describe a case of ALK-RCC in a 76-year-old female. The tumour was composed of discohesive rhabdoid cells and pleomorphic, multinucleated cells (equivalent to ISUP/WHO grade 4). The tumour showed expression with PAX8, Keratin 7 and alpha methylacyl CoA racemase. ALK (D5F3 clone) was strongly and diffusely positive. ALK-FISH showed significant split signals of ALK, confirming the diagnosis. RNA sequencing showed TPM3::ALK rearrangement. Including the current case, there are 14 reported ALK-RCC cases with the same TPM3 fusion partner gene. Review of these published cases highlights their morphological heterogeneity and stresses the importance of running ALK immunohistochemistry on difficult cases to classify renal tumours. This is important while identification of ALK-RCC has clinical significance due to the availability of targeted therapy with ALK inhibitors.