Life-threatening hypertriglyceridemia-induced pancreatitis related to alectinib successfully treated by plasmapheresis: A review of the literature on metabolic toxicities associated with anaplastic lymphoma kinase inhibitors

2020 ◽  
Vol 26 (6) ◽  
pp. 1533-1537 ◽  
Author(s):  
Arundati Rao ◽  
Aswanth Reddy ◽  
Corey Dinunno ◽  
Ibrahim Elali

Introduction Actionable mutations are tested as standard of care for all new metastatic non-small cell lung cancers. Tumors harboring an anaplastic lymphoma kinase mutation respond to tyrosine kinase inhibitors targeting anaplastic lymphoma kinase pathway. Patients are monitored for common adverse effects, although we occasionally encounter unexpected side effects. Case report A 52-year-old male presented with a right hilar lung mass, and workup revealed a stage IIIA adenocarcinoma. He underwent treatment with concurrent chemoradiation; however, disease recurred one year later with a right hilar mass and contralateral mediastinal lymphadenopathy, biopsy of which resulted positive for adenocarcinoma. Molecular analysis showed anaplastic lymphoma kinase rearrangement and alectinib was started. Six months into therapy, he presented with hematochezia, nausea, and epigastric pain and was diagnosed with acute pancreatitis. Triglyceride level resulted above the measurable level at >5680mg/dL, thought to be the inciting event of pancreatitis. Management and outcome: Despite treatment with intravenous hydration, insulin infusion, and antibiotics, he decompensated with development of respiratory failure, shock requiring intensive care. Therapeutic plasmapheresis was initiated due to persistently elevated triglyceride. Following the third plasmapheresis, triglyceride level decreased to 359 mg/dL. With aggressive multidisciplinary management, he made a complete recovery. Follow-up imaging studies at three and six months show a stable mass-like abnormality in the right hilum without evidence of disease progression. Discussion Prior to starting alectinib, our patient’s triglyceride level was 420 mg/dL. While he consumed alcohol, he had no other traditional risk factor. To our knowledge, this is the first reported case of hypertriglyceridemia-induced acute pancreatitis related to treatment with an anaplastic lymphoma kinase inhibitor.

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257718
Author(s):  
Yoko Ota ◽  
Hiroyuki Yoda ◽  
Takahiro Inoue ◽  
Takayoshi Watanabe ◽  
Yoshinao Shinozaki ◽  
...  

Anaplastic lymphoma kinase (ALK) aberration is related to high-risk neuroblastomas and is an important therapeutic target. As acquired resistance to ALK tyrosine kinase inhibitors is inevitable, novel anti-ALK drug development is necessary in order to overcome potential drug resistance against ATP-competitive kinase inhibitors. In this study, to overcome ALK inhibitor resistance, we examined the growth inhibition effects of newly developed ALK-targeting pyrrole-imidazole polyamide CCC-003, which was designed to directly bind and alkylate DNA within the F1174L-mutated ALK gene. CCC-003 suppressed cell proliferation in ALK-mutated neuroblastoma cells. The expression of total and phosphorylated ALK was downregulated by CCC-003 treatment but not by treatment with a mismatch polyamide without any binding motif within the ALK gene region. CCC-003 preferentially bound to the DNA sequence with the F1174L mutation and significantly suppressed tumor progression in a human neuroblastoma xenograft mouse model. Our data suggest that the specific binding of CCC-003 to mutated DNA within the ALK gene exerts its anti-tumor activity through a mode of action that is distinct from those of other ALK inhibitors. In summary, our current study provides evidence for the potential of pyrrole-imidazole polyamide ALK inhibitor CCC-003 for the treatment of neuroblastoma thus offering a possible solution to the problem of tyrosine kinase inhibitor resistance.


Author(s):  
Saranyadevi Subburaj ◽  
Tanvi Anand Nagrale ◽  
Mohd. Mustufa Khan ◽  
Nivya James ◽  
Ramanathan Karuppasamy ◽  
...  

RSC Advances ◽  
2018 ◽  
Vol 8 (30) ◽  
pp. 16470-16493 ◽  
Author(s):  
Muhammad Latif ◽  
Zaman Ashraf ◽  
Sulman Basit ◽  
Abdul Ghaffar ◽  
Muhammad Sohail Zafar ◽  
...  

This review describes hit-to-drug evolution milestones, synthetic strategies and clinical significance of novel DAAPalogues discovered for ALK inhibition which are either progressing as investigational or preclinical candidates to treat the patients with ALK+-NSCLC.


Pharmacology ◽  
2020 ◽  
Vol 105 (11-12) ◽  
pp. 715-718
Author(s):  
Abigail R. Bland ◽  
Nensi Shrestha ◽  
Rhonda J. Rosengren ◽  
John C. Ashton

Crizotinib is a tyrosine kinase inhibitor used to treat anaplastic lymphoma kinase-positive lung cancer. There is in vitro evidence that crizotinib may auto-inhibit cytochrome P450 3A (CYP3A) activity, with important implications for crizotinib pharmacokinetics. In order to test whether crizotinib treatment alters CYP3A activity in vivo, mice were treated with 5 and 25 mg/kg crizotinib (p.o.) daily for 14 days. Results showed that crizotinib treatment did not alter CYP3A activity as determined by erythromycin <i>N</i>-demethylation. In addition, CYP3A polypeptide expression as measured by Western blot was unchanged. Therefore, our results do not support CYP3A inhibition by crizotinib in vivo.


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