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P-Glycoprotein (ABCB1/MDR1) and BCRP (ABCG2) Limit Brain Accumulation and Cytochrome P450-3A (CYP3A) Restricts Oral Exposure of the RET Inhibitor Selpercatinib (RETEVMO).

ABSTRACT: Selpercatinib is a targeted, FDA-approved, oral, small-molecule inhibitor for the treatment of rearranged during transfection (RET) proto-oncogene mutation-positive cancer. Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A complex in selpercatinib pharmacokinetics. Selpercatinib was efficiently transported by hABCB1 and mAbcg2, but not hABCG2, and was not a substrate of human OATP1A2, -1B1 or -1B3 in vitro. In vivo, brain and testis penetration were increased by 3.0- and 2.7-fold in Abcb1a/1b^-/- mice and by 6.2- and 6.4-fold in Abcb1a/1b;Abcg2^-/- mice, respectively. Oatp1a/1b deficiency did not alter selpercatinib pharmacokinetics. The ABCB1/ABCG2 inhibitor elacridar boosted selpercatinib brain penetration in wild-type mice to the levels seen in Abcb1a/1b;Abcg2^-/- mice. Cyp3a^-/- mice showed a 1.4-fold higher plasma AUC_0-4h than wild-type mice, which was then 1.6-fold decreased upon transgenic overexpression of human CYP3A4 in liver and intestine. In summary, ABCG2, and especially ABCB1, limit brain and testis penetration of selpercatinib. Elacridar coadministration could mostly reverse these effects, without causing acute toxicity. CYP3A-mediated metabolism can limit selpercatinib oral exposure and hence its tissue concentrations. These insights may be useful in the further clinical development of selpercatinib.

SUBMITTER: Wang Y

PROVIDER: S-EPMC8617681 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To evaluate ATP-binding cassette (ABC) transporters in colonic pathophysiology as they had recently been related to colorectal cancer (CRC) development.Literature search was conducted on PubMed using combinations of the following terms: ABC transporters, ATP binding cassette transporter proteins, inflammatory bowel disease, ulcerative, colitis, Crohn's disease, colorectal cancer, colitis, intestinal inflammation, intestinal carcinogenesis, ABCB1/P-glycoprotein (P-gp/CD243/MDR1), ABCC2/multidrug resistance protein 2 (MRP2) and ABCG2/breast cancer resistance protein (BCRP), Abcb1/Mdr1a, abcc2/Mrp2, abcg2/Bcrp, knock-out mice, tight junction, membrane lipid function.Recently, human studies reported that changes in the levels of ABC transporters were early events in the adenoma-carcinoma sequence leading to CRC. A link between ABCB1, high fat diet and gut microbes in relation to colitis was suggested by the animal studies. The finding that colitis was preceded by altered gut bacterial composition suggests that deletion of Abcb1 leads to fundamental changes of host-microbiota interaction. Also, high fat diet increases the frequency and severity of colitis in specific pathogen-free Abcb1 KO mice. The Abcb1 KO mice might thus serve as a model in which diet/environmental factors and microbes may be controlled and investigated in relation to intestinal inflammation. Potential molecular mechanisms include defective transport of inflammatory mediators and/or phospholipid translocation from one side to the other of the cell membrane lipid bilayer by ABC transporters affecting inflammatory response and/or function of tight junctions, phagocytosis and vesicle trafficking. Also, diet and microbes give rise to molecules which are potential substrates for the ABC transporters and which may additionally affect ABC transporter function through nuclear receptors and transcriptional regulation. Another critical role of ABCB1 was suggested by the finding that ABCB1 expression identifies a subpopulation of pro-inflammatory Th17 cells which were resistant to treatment with glucocorticoids. The evidence for the involvement of ABCC2 and ABCG2 in colonic pathophysiology was weak.ABCB1, diet, and gut microbes mutually interact in colonic inflammation, a well-known risk factor for CRC. Further insight may be translated into preventive and treatment strategies.

Project description:BackgroundOverexpression of ABC transporters is a big challenge on cancer therapy which will lead cancer cells resistance to a series of anticancer drugs. Gedatolisib is a dual PI3K and mTOR inhibitor which is under clinical evaluation for multiple types of malignancies, including colorectal cancer. The growth inhibitory effects of gedatolisib on colorectal cancer cells have been specifically studied. However, the role of ABC transporters on gedatolisib resistance remained unclear. In present study, we illustrated the role of ABC transporters on gedatolisib resistance in colorectal cancer cells.MethodsCell viability investigations of gedatolisib on colorectal cancer cells were determined by MTT assays. The verapamil and Ko143 reversal studies were determined by MTT assays as well. ABCB1 and/or ABCG2 siRNA interference assays were conducted to verify the role of ABCB1- and ABCG2-overexpression on gedatolisib resistance. The accumulation assays of gedatolisib were conducted using tritium-labeled paclitaxel and mitoxantrone. The effects of gedatolisib on ATPase activity of ABCB1 or ABCG2 were conducted using PREDEASY ATPase Kits. The expression level of ABCB1 and ABCG2 after gedatolisib treatment were conducted by Western blotting and immunofluorescence assays. The well-docked position of gedatolisib with crystal structure of ABCB1 and ABCG2 were simulated by Autodock vina software. One-way ANOVA was used for the statistics analysis.ResultsGedatolisib competitively increased the accumulation of tritium-labeled substrate-drugs in both ABCB1- and ABCG2-overexpression colorectal cancer cells. Moreover, gedatolisib significantly increased the protein expression level of ABCB1 and ABCG2 in colorectal cancer cells. In addition, gedatolisib remarkably simulated the ATPase activity of both ABCB1 and ABCG2, suggesting that gedatolisib is a substrate drug of both ABCB1 and ABCG2 transporters. Furthermore, a gedatolisib-resistance colorectal cancer cell line, SW620/GEDA, was selected by increasingly treatment with gedatolisib to SW620 cells. The SW620/GEDA cell line was proved to resistant to gedatolisib and a series of chemotherapeutic drugs, except cisplatin. The ABCB1 and ABCG2 were observed overexpression in SW620/GEDA cell line.ConclusionsThese findings suggest that overexpression of ABCB1 and ABCG2 may restrict the efficacy of gedatolisib in colorectal cancer cells, while co-administration with ABC transporter inhibitors may improve the potency of gedatolisib.

Project description:BackgroundRET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown.MethodsWe enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.ResultsIn the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events.ConclusionsIn this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

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P-Glycoprotein (ABCB1/MDR1) and BCRP (ABCG2) Limit Brain Accumulation and Cytochrome P450-3A (CYP3A) Restricts Oral Exposure of the RET Inhibitor Selpercatinib (RETEVMO).

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