Compositions and methods for treating RAS-mutant cancers
The present disclosure relates generally to compositions and methods for the treatment of a RAS-mutant cancer. In particular, the present technology relates to administering a therapeutically effective amount of one or more TXNRD1 inhibitors to a subject diagnosed with, or at risk for a RAS-mutant cancer (e.g., RAS-mutant pancreatic cancer).
1 . A method for treating a RAS-mutant cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a thioredoxin reductase 1 (TXNRD1) inhibitor selected from the group consisting of auranofin, Piperlongumine, (Diphenyl-2-thienylphosphine-κP) [2-(4-methoxyphenyl) ethynyl]gold (D9), 2-((4-Chlorophenyl) sulfonyl)-6-methoxy-3-nitropyridine (TRi-1), Myricetin, 4-(benzothiazol-2-yl)-4-hydroxycyclohexa-2,5-dienone (PMX464), 1-methylpropyl 2-imidazolyl disulfide (PX12), brevetoxin-2, manumycin A, ethaselen, aurothioglucose, protoporphyrin IX, an anti-TXNRD1 antibody, and
and an additional therapeutic agent, wherein the additional therapeutic agent is gemcitabine or a KRAS G12C inhibitor, wherein the KRAS G12C inhibitor is sotorasib (AMG 510).
2 . The method of claim 1 , wherein the subject displays elevated expression levels of RAS protein in cancer cells prior to treatment.
3 . The method of claim 1 , wherein the RAS-mutant cancer is lung cancer, mucinous adenoma, pancreatic cancer, colorectal cancer, skin cancer, endometrial cancer, testicular germ cell cancer, or adrenal gland cancer.
4 . The method of claim 3 , wherein the RAS-mutant cancer comprises a KRAS, NRAS, or HRAS mutation selected from the group consisting of G12C, G12D, G12V, G12A, G12S, G12R, G13D, G13C, G13S, G13R, G13A, G13V, Q61H, Q61L, Q61R, Q61K, Q61P, and Q61E.
5 . The method of claim 1 , wherein the subject exhibits one or more signs or symptoms selected from among pain in the upper abdomen that radiates towards the back, loss of appetite or unintended weight loss, depression, new-onset diabetes, blood clots, fatigue, yellowing of skin and the whites of eyes (jaundice), bloating, nausea, and vomiting.
6 . The method of claim 1 , wherein the subject harbors one or more point mutations in TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A, SF3B1, EPC1, ARID2, ATM, ZIM2, MAP2K4, NALCN, SLC16A4, MAGEA6, ROBO2, KDM6A, PREX2, ERBB2, MET, FGFR1, CDK6, PIK3R3, PIK3CA, BRCA1, BRCA2, or PALB2.
7 . The method of claim 1 , wherein the subject is human.
8 . The method of claim 1 , wherein the TXNRD1 inhibitor is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, iontophoretically, transmucosally, or intramuscularly.
9 . The method of claim 1 , wherein the TXNRD1 inhibitor or the inhibitory nucleic acid is administered daily for 6 weeks or more, or is administered daily for 12 weeks or more.