Biology subjects

KHAN, S.

Publications and source records attributed to KHAN, S..

3 recordsLinked to original sources

bioRxiv2026

The combination of BCL-xL PROTAC and mTOR inhibitor sensitizes pancreatic ductal adenocarcinoma to KRASG12D inhibitor treatment by enhancing apoptosis induction

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a five-year survival rate of approximately 13%, partly because of limited treatment options and resistance to therapies. Although the recently discovered KRAS G12D inhibitor MRTX1133 has shown promise for PDAC treatment in preclinical studies, its clinical efficacy as a single agent is expected to be limited, as is the case with KRAS G12C inhibitors. Therefore, in this study, we evaluated potential combination strategies to enhance the therapeutic effect of MRTX1133. We rationally combined MRTX1133 with the BCL-xL proteolysis-targeting chimera (PROTAC) DT2216 and the mTOR inhibitor everolimus, which significantly potentiated the anti-tumor activity of MRTX1133 in multiple G12D-mutated PDAC cells in vitro by enhancing apoptosis induction. Mechanistically, MRTX1133 treatment increased BIM and decreased NOXA levels, while the combination of DT2216/everolimus was shown to simultaneously enhance BIM release and stabilize NOXA. In vivo, DT2216/everolimus combination significantly potentiated the anti-tumor activity of MRTX1133 in AsPC1 PDAC xenograft model. Furthermore, the triple combination of MRTX1133, DT2216, and everolimus effectively overcame acquired resistance to MRTX1133 in AsPC1 cells in vitro and in xenograft model. Collectively, our findings suggest that the single-agent efficacy of MRTX1133 is limited by apoptosis inhibition, and that its combination with DT2216/everolimus can enhance apoptosis and potentially overcome resistance in KRAS G12D-mutated PDAC. SIGNIFICANCEKRAS inhibitors, including KRAS G12D inhibitor MRTX1133, are promising therapeutics against KRAS-mutated pancreatic ductal adenocarcinoma (PDAC), but drug resistance limits their efficacy. Our study reveals that robust induction of apoptosis using a combination of BCL-xL PROTAC degrader and an mTOR inhibitor, significantly enhances MRTX1133 efficacy in PDAC models without increasing toxicity to normal tissues.

cancer biology↗

bioRxiv2022

Co-targeting BCL-XL and MCL-1 with DT2216 and AZD8055 synergistically inhibits small-cell lung cancer growth without causing on-target toxicities in mice

Small-cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. The dismal prognosis in SCLC is in part associated with an upregulation of BCL-2 family anti-apoptotic proteins, including BCL-XL and MCL-1. Unfortunately, the currently available inhibitors of BCL-2 family anti-apoptotic proteins, except BCL-2 inhibitors, are not clinically relevant because of various on-target toxicities. We, therefore, aimed to develop an effective and safe strategy targeting these anti-apoptotic proteins with DT2216 (our platelet-sparing BCL-XL degrader) and AZD8055 (an mTOR inhibitor) to avoid associated on-target toxicities while synergistically optimizing tumor response. Through BH3 mimetic screening, we identified a subset of SCLC cell lines that is co-dependent on BCL-XL and MCL-1. After screening inhibitors of selected tumorigenic pathways, we found that AZD8055 selectively downregulates MCL-1 in SCLC cells and its combination with DT2216 synergistically killed BCL-XL/MCL-1 co-dependent SCLC cells, but not normal cells. Mechanistically, the combination caused BCL-XL degradation and suppression of MCL1 expression, and thus disrupted MCL-1 interaction with BIM leading to an enhanced apoptotic induction. In vivo, DT2216+AZD8055 combination significantly inhibited the growth of cell line-derived and patient-derived xenografts and reduced tumor burden accompanied with extended survival in a genetically-engineered mouse (GEM) model of SCLC without causing significant thrombocytopenia or other normal tissue injury. Thus, these preclinical findings lay a strong foundation for future clinical studies to test DT2216+mTOR inhibitor combination in a subset of SCLC patients whose tumors are co-driven by BCL-XL and MCL-1.

cancer biology↗

bioRxiv2019

Dillenia indica fruit extract has Glucose and Cholesterol Lowering effects

BackgroundDillenia indica (D. indica) can suppress carbohydrates hydrolysis by inhibiting -amylase and -glucosidase. However, there is a lack of understanding of its therapeutic potential as an antidiabetic and anti-hyperlipidemic agent. Methods and findingsType 2 diabetes (T2D) was induced by a single intraperitoneal injection of Streptozotocin (STZ; 90mg/kg) and hyperlipidemia by feeding with 1% cholesterol, 5% coconut oil and 5% cow fat diet. Administration of D. indica extracts in water for four weeks triggered a significant (p[≤]0.05) reduction in fasting serum glucose (FSG) levels with concomitant improvement in serum insulin levels. Both the water- and ethanol-extract of D. indica treated groups showed significant (p[≤]0.01) reduction in total cholesterol levels by 25% and 19%, respectively. HDL-cholesterol was also augmented (by 14%) in ethanol-extract treated group. Liver glycogen content was higher in the water-extract treated group. Histopathological examination revealed that there was no tubular epithelial cell degeneration or necrosis in the renal tissues or hepatocyte degeneration and sinusoidal dilation in liver tissues in animals that received the water-extract. On the other hand, consumption of D. indica extract with 1% cholesterol, 5% coconut oil diet or with a 5% cow fat diet for 14 days significantly reduced serum cholesterol levels in group-lll (60[->]45 mg/dl; p[≥]0.05) and -IV (85[->]66 mg/dl; p[≥]0.05) hypercholesterolemic model rats. D. indica fruit extract also reduced serum TG levels (Group-III: 87[->]65 mg/dl; Group-IV: 40[->]90 mg/dl; p[≥]0.05). Interestingly, treatment with D. indica prevented a reduction in serum HDL levels in those hypercholesterolemic model rats. Serum LDL levels were significantly lower in group-III (47[->]39 mg/dl; p[≥]0.05) and group-IV (57[->]44 mg/dl; p[≥]0.05) hypercholesterolemic model rats after D. indica treatment. ConclusionD. indica fruit ameliorates FSG, insulin secretion, glycogen synthesis, and serum lipid profile. Therefore, D. indica fruit can be a potential therapeutic agent for diabetic and hyperlipidemia. Graphical AbstractExtract of D. indica in water reduces FSG, serum insulin levels, and ameliorates the serum lipid profile in diabetic model rats without any adverse effects on kidney and liver tissues. Extract of D. indica in ethanol significantly reduces serum cholesterol, TG, LDL with no reduction in HDL levels in hyper-lipidemic model rats. HighlightsO_LID. indica fruit extracts diminished fasting serum glucose (FSG) levels in STZ-induced type 2 diabetic model rats C_LIO_LID. indica fruit extracts boosted insulin secretion C_LIO_LID. indica fruit extracts showed no toxic effects on the kidney and the liver functions C_LIO_LIExtract in water was more effective in reducing FSG levels than extract in ethanol C_LIO_LIChronic consumption of 1% cholesterol, 5% coconut oil and 5% cow fat diet was sufficient to make the rat hypercholesterolemic C_LIO_LID. indica fruit extract has the potential to reduce serum cholesterol, TG, LDL with prevention in reduction in serum HDL levels. C_LI

pharmacology and toxicology↗