Results:
MOLM-14 FLT-ITD mutant cells selected for resistance to TUS over a 3-month period developed 61-fold greater resistance (IC50 parental cells 2.3 ± 0.3 nM; resistant cells 140.3 ± 28.7 nM, mean ± SEM). Resistance levels remained stable when tested at 60 days after drug removal. TUS-resistant cells (TUS/R) were 60-fold resistant to gilteritinib (FLT3 inhibitor) but not to quizartinib (FLT3 inhibitor). There was no observed resistance to azacitidine, luxeptinib (lymphoid & myeloid kinaseinhibitor), brequinar (DHODH inhibitor), zelavespib (HSP90 inhibitor), or IMP-1088 (NMT1/2 inhibitor), and a small degree of hypersensitivity (<2-fold) of TUS/R cells to luxeptinib, brequinar, and IMP-1088. Unexpectedly, TUS/R cells were ~2,000-fold hypersensitive to venetoclax, indicating that resistanceto TUS created a substantial synthetic lethal vulnerability to venetoclax. Initial western blotanalysis of parental cells in theabsence of TUS and TUS/R cells immediately after removal from 75 nM TUS, demonstrated that pFLT3 was markedly inhibited in the parental and TUS/R cells but that pERK1/2, pSYK and pSTAT5 levels were all elevated relativeto thetotal protein level of each kinase. Since FLT3 activity remained fully inhibited, TUS resistance was associated a FLT3-independent mechanism thataltered multiplesignaling pathways. TUS/R cells had a large increase in BAX suggesting a basis for the marked hypersensitivity to venetoclax. Additional analysis of pro-and anti-apoptotic proteins will be updated at the meeting.
"2,000-fold hypersensitive to venetoclax" is something. Interesting that "TUS-resistant cells (TUS/R) were 60-fold resistant to gilteritinib (FLT3 inhibitor) but not to quizartinib (FLT3 inhibitor)." And to Luxeptinib BTW.
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