6/12/2023 0 Comments Reddit arq![]() ![]() Based on recent literature showing a direct link of venetoclax sensitivity to electron transport chain activity, co-treatment with IACS-010759, a mitochondrial complex I inhibitor, was also tested, showing moderate enhancement of anti-BCL-2 activity. LP-118, a Novel BCL2 Inhibitor, Shows Potent in Vitro Anti-Myeloma Activity (ASH 2022) - P1 | "LP-118 is a novel BCL-2/BCL-XL inhibitor, which has a modified structure with fine-tuned BCL-XL activity that minimizes platelet toxicity, associated with other BCL-XL inhibitors, such as navitoclax.In cell lines with acquired venetoclax resistance, the combinations of LP-118 with bortezomib or dexamethasone also showed promising synergistic activity, but requiring higher doses of both compounds in comparison to their venetoclax-sensitive counterparts. ![]() ![]() Thus, these combinations may be effective in patients showing intrinsic tolerance to multiple drugs." These data suggest that defective ISR signaling may be a factor in TP53 mut AML treatment outcome and point to DELE1 dysregulation as a driver of ISR."ĭrug Combinations Co-Targeting Myeloid Cell Leukemia-1 (Mcl-1) Protein Can Overcome Microenvironmentally-Induced Multi-Drug Tolerance in Non-Hodgkin Lymphomas (ASH 2018) - P1 "Ibrutinib (IBR), an inhibitor of Bruton's Tyrosine Kinase (Btk) and venetoclax (VEN), an inhibitor of Bcl-2 have been used in Chronic Lymphocytic Leukemia (CLL), but single agent responses to these drugs are often incomplete and not durable.Results showed that inhibitors of apoptotic proteins (A1155643, VEN, ABT737), IRAK4 (CA-4948, compound 26, and AS2444697), intracellular TLRs (chloroquine), Hsp90 (ganetespib), CDK (ribociclib), proteasome (bortezomib), Btk (IBR), AKT (MK2206), and HDAC (SAHA and panobinostat) or activator of PP2A (DBK1532 and NZ8061) were synergistically toxic with Mcl-1 inhibitor (S63845) in CLL cells.Drug combinations targeting Mcl-1 and proteasome, IRAK4, TLRs, Btk, Hsp90, or CDK selectively overcame multi-drug tolerance in CLL cells. However, larger patient cohorts."ĭELE1 LOSS AND DYSFUNCTIONAL INTEGRATED STRESS SIGNALING IN TP53 MUTATED AML IS A NOVEL PATHWAY FOR VENETOCLAX RESISTANCE (EHA 2023) - P1/2, P1b, P3 | "Background: Venetoclax (ven) in combination with hypomethylating agents or low dose cytarabine leads to rapid and durable remission in patients (pts) with acute myeloid leukemia (AML) unfit for intensive chemotherapy (IC), however, pts with TP53 mutations ( TP53 mut ) exhibit adverse prognosis.Deletion of DELE1 or OMA1 in AML cell lines blocked eIF2α activation and induction of the transcription factor ATF4, a critical ISR effector, in response to the mitochondrial stressor FCCP, ven, and azacitidine, and resulted in ven resistance similar to that of TP53 deficient cells.Further screening of these cell lines for ven sensitizing activity revealed the BH3 mimetic S63845, which targets MCL1, as the top hit, suggesting that combined BH3 mimetics may overcome ven resistance during ISR pathway defects. In contrast, our BH3 mimetic drug screening results demonstrated that the dual inhibition of BCL-2 and BCL-XL by navitoclax is capable of inducing apoptosis in myeloid blast cells regardless of TP53 mutation status. This study showed that AML patients harboring TP53 mutations have reduced ex vivo sensitivity to venetoclax, which might be associated with decreased BCL-2 protein expression. In the computational comparison analysis of VenEx trial participants' genetic aberrations and BH3 mimetic ex vivo responses, TP53 mutation (p=0.005) and complex karyotype (p=0.003) were the strongest predictors of venetoclax resistance, while IDH2 (p=0.006) and SRSF2 (p=0.007) mutations predicted favorable responses (Figure A). BCL-2/BCL-XL INHIBITION INDUCES APOPTOSIS AND CIRCUMVENTS VENETOCLAX RESISTANCE IN TP53-MUTATED ACUTE MYELOID LEUKEMIA (EHA 2023) - P2 | " 109 AML samples' blast-specific ex vivo responses to venetoclax (BCL-2 inhibitor), navitoclax (BCL-2/BCL-XL inhibitor), A-1331852 (BCL-XL inhibitor) and S-63845 (MCL-1 inhibitor) were profiled by flow cytometry. ![]()
0 Comments
Leave a Reply. |