Larotrectinib, sold under the brand name Vitrakvi, is a medication for the treatment of cancer. It is an inhibitor of tropomyosin kinase receptors TrkA, TrkB, and TrkC. It was discovered by Array BioPharma and licensed to Loxo Oncology in 2013. Larotrectinib was initially awarded orphan drug status in 2015, for soft tissue sarcoma, and breakthrough therapy designation in 2016 for the treatment of metastatic solid tumors with NTRK fusion. Some clinical trial results were announced in 2017. On 26 November 2018, Larotrectinib was approved by the FDA.Larotrectinib was the first drug to be specifically developed and approved to treat any cancer containing certain mutations, as opposed to cancers of specific tissues (i.e., the approval is "tissue agnostic"). Several earlier drugs, including pembrolizumab, were eventually approved by the FDA for treatment of specific mutations independent of the type of cancer, but those drugs had been initially developed for specific cancer types. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.Phase II clinical trials evaluating the drug for efficacy and safety in treating several types of solid tumors are ongoing.Larotrectinib was approved for medical use in the European Union in September 2019. It was approved for medical use in Australia in August 2020. References
External links
"Larotrectinib". Drug Information Portal. U.S. National Library of Medicine. "Larotrectinib sulfate". National Cancer Institute. "Larotrectinib sulfate". NCI Dictionary of Cancer Terms. National Cancer Institute.
MDDS is associated with mutations in the genes TK2, SUCLA2, RRM2B, DGUOK, POLG, TYMP, SUCLG1,  and TWNK.Myopathic MDS is strongly correlated to a variety of mutations in the gene TK2, seeing a reduction of TK2 activity to less than 32% in people with MDS found with the mutation. Because TK2 plays a key role in the mitochondrial salvage pathways of several deoxyribonucleoside triphosphates (dNTPs), a lowered activity would lead to less cycling of nucleotides. This lack of nucleotide recycling is detrimental since the mitochondria cannot synthesize entirely new deoxynucleotides, and the inner membrane of the mitochondria prevents the negatively charged nucleotides of the cytosol from entering.The SUCLA2 gene codes for the beta-subunit of SCS-A. This enzyme catalyzes the synthesis of succinate and coenzyme A into succinyl-CoA, but is also associated with the complex formed by nucleoside diphosphate kinase (NDPK) in the last step of the dNTP salvage pathway.The RRM2B gene, which is expressed in the cell nucleus, codes for one of two versions of the R2 subunit of ribonucleotide reductase, which generates nucleotide precursors required for DNA replication by reducing ribonucleoside diphosphates to deoxyribonucleoside diphosphates. The version of R2 encoded by RRM2B is induced by TP53, and is required for normal DNA repair and mtDNA synthesis in non-proliferating cells. The other form of R2 is expressed only in dividing cells.The DGUOK gene encodes for mitochondrial deoxyguanosine kinase (dGK), which catalyzes the phosphorylation of deoxyribonucleosides into nucleotides.