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Selpercatinib is a RET receptor tyrosine kinase inhibitor for the treatment of RET-driven non-small cell lung cancer, medullary thyroid cancer, and thyroid cancer in appropriate patient populations.
Selpercatinib is a RET receptor tyrosine kinase inhibitor for the treatment of RET-driven non-small cell lung cancer, medullary thyroid cancer, and thyroid cancer in appropriate patient populations.
Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase containing extracellular, transmembrane, and intracellular domains whose activity is required for normal kidney and nervous system development. Constitutive RET activation is primarily achieved through chromosomal rearrangements producing 5' fusions of dimerizable domains to the 3' RET tyrosine kinase domain, such as KIF5B-RET and CCDC6-RET, resulting in constitutive dimerization and subsequent autophosphorylation. Constitutive activation leads to increased downstream signalling and is associated with tumour invasion, migration, and proliferation. Selpercatinib is a direct RET kinase inhibitor, exhibiting IC values between 0.92 and 67.8 nM depending on the exact RET genotype. Information based on natural as well as induced resistance mutations and molecular modelling suggests that selpercatinib directly inhibits RET autophosphorylation by competing with ATP for binding. Various single amino acid mutations at position 810 inhibit selpercatinib binding without significantly altering ATP binding, potentially leading to treatment failures. Selpercatinib is also reported to inhibit other tyrosine kinase receptors, including VEGFR1, VEGFR3, FGFR1, FGFR2, and FGFR3, at clinically relevant concentrations. The significance of these effects is not well studied.
Selpercatinib is approved to treat: Selpercatinib is currently approved for these indications under an accelerated approval scheme and continued approval may be contingent on future confirmatory trials.
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