Acute kidney Injury due to Alectinib, an Anaplastic Lymphoma Kinase inhibitor

Introduction: The array of unintended effects of targeted oncological treatments is still being elucidated. Cognizance of these effects is important since they allow early identification and intervention. Methods: We report a case of progressive reduction in kidney function following the introduction of the oral second generation Anaplastic Lymphoma Kinase (ALK) Inhibitor: Alectinib for the treatment of metastatic non-small cell carcinoma of the lung (NSCLC). Kidney biopsy findings suggested that the predominant manifestation was acute tubular injury, which resolved with cessation of Alectinib therapy and did not recur with the introduction of the third generation ALK inhibitor Lorlatinib. Conclusions: This case report adds to the Onco-Nephrology literature in relation to the potential nephrotoxic effects of ALK inhibitors.

Inhibition of Plasmodium falciparum Lysyl-tRNA synthetase via an anaplastic lymphoma kinase inhibitor

Aminoacyl-tRNA synthetases are attractive targets for the development of antibacterial, antifungal, antiparasitic agents and for the treatment of other human diseases. Lysyl-tRNA synthetase (LysRS) from this family has been validated as a promising target for the development of antimalarial drugs. Here, we developed a high-throughput compatible assay and screened 1215 bioactive compounds to identify Plasmodium falciparum cytoplasmic LysRS (PfLysRS) inhibitor. ASP3026, an anaplastic lymphoma kinase inhibitor that was used in clinical trials for the treatment of B-cell lymphoma and solid tumors, was identified as a novel PfLysRS inhibitor. ASP3026 suppresses the enzymatic activity of PfLysRS at nanomolar potency, which is >380-fold more effective than inhibition of the human counterpart. In addition, the compound suppressed blood-stage P. falciparum growth. To understand the molecular mechanism of inhibition by ASP3026, we further solved the cocrystal structure of PfLysRS-ASP3026 at a resolution of 2.49 Å, providing clues for further optimization of the compound. Finally, primary structure-activity relationship analyses indicated that the inhibition of PfLysRS by ASP3026 is highly structure specific. This work not only provides a new chemical scaffold with good druggability for antimalarial development but also highlights the potential for repurposing kinase-inhibiting drugs to tRNA synthetase inhibitors to treat human diseases.

EML4-ALK, a potential therapeutic target that responds to alectinib in ovarian cancer

Ovarian cancer is prone to recurrence and chemotherapy resistance. Ovarian tumours of some patients have been positive for anaplastic lymphoma kinase fusion gene expression (ALK+). Preclinical studies indicate that anaplastic lymphoma kinase inhibitor can suppress the growth of ovarian cancer cells and transplantation tumours. Here, we present a patient with metastatic ALK+ high-grade serous ovarian cancer that testing positive for EML4-ALK (microtubule-associated protein-like 4 gene, fused to the anaplastic lymphoma kinase gene), experienced dramatic benefit after administration of the anaplastic lymphoma kinase inhibitor alectinib. This is the first clinical evidence that treatment with alectinib may provide a personalized maximum benefit for patients with high-grade serous ovarian cancer who are positive for EML4-ALK.

A Novel ALK Fusion Gene (NSF-ALK) Identified in a Patient With Recurrent Spindle Cell Sarcoma Respond to Crizotinib: A Case Report

Background: Spindle cell sarcoma (SCS) is a rare malignant tumor which relapses quickly and has poor prognosis.Case presentation: We report a case of SCS deriving from the left side of chestpossessed a novel unreported ALK fusion gene named NSF-ALK found by Next Generation Sequencing (NGS) technology. Despite receiving three surgical resections, local recurrence occurred rapidly and distant brain metastasis was eventually observed in this patient. The subsequent administration of crizotinib1, an oral anaplastic lymphoma kinase inhibitor, resulted in dramatic tumor shrinkage and the patient entered a remission period that has been ongoing for more than 10 months.Conclusions: In summary, this study is the first to describe a novel NSF-ALK fusion in spindle cell sarcoma which has promising efficacy by crizotinib treatment. More importantly, the case also shows that next generation sequencing provids more information of mutation to guide treatment in clinical decisions by presenting molecular changes.