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- chloroquine phosphate / Generic mfg.
ROLE OF AUTOPHAGY IN COLONIC MUCUS SECRETION IN PATIENTS WITH ULCERATIVE COLITIS AND HEALTHY SUBJECTS. (South Hall A, Poster Hall - McCormick Place) - Mar 23, 2023 - Abstract #DDW2023DDW_2977;
b) by pharmacologic approach using known autophagy inhibitors including Bafilomycin A1 (BafA1, a vacuolar ATPase inhibitor) and Chloroquine (a lysosometropic agent)... We conclude that autophagy modulates mucus secretion in health and UC.
- FERRIC MALTOL BLOCKS INTESTINAL MUCOSAL INFLAMMATION THROUGH INDUCING ELMO1/FTH1-MEDIATED FERRITINOPHAGY OF PATHOGENIC TH17 CELL IN INFLAMMATORY BOWEL DISEASE. (South Hall A, Poster Hall - McCormick Place) - Mar 23, 2023 - Abstract #DDW2023DDW_2731;
We conclude that autophagy modulates mucus secretion in health and UC. We shed light on the mechanism of ELMO1-mediated ferritinophagy and provided that ferric maltol combined with vitamin C might help improve the management of patients with IBD.
- FUNCTIONAL ROLE OF GASTRIC-COMMENSAL BACTERIA IN THE DEVELOPMENT OF CD44V9-POSITIVE CANCER STEM-LIKE CELLS IN H. PYLORI-INFECTED GASTRIC MUCOSA (S104 - McCormick Place) - Mar 23, 2023 - Abstract #DDW2023DDW_1933;
Butyrate produced by Streptococcus spp. fosters development of CD44v9-positive cancer stem-like cells in H. pylori -infected stomach tissue through the enhancement of CAPZA1 expression.
- | bortezomib / Generic mfg., JQ-1 / Roche, sirolimus / Generic mfg.
Journal: JQ-1/Bortezomib combination strongly impairs MM and PEL survival by inhibiting c-Myc and mTOR despite the activation of pro-survival mechanisms. (Pubmed Central) - Mar 21, 2023
However, besides the pro-death effects, JQ-1/Bortezomib activated UPR and autophagy as pro-survival mechanisms. In conclusion this study demonstrates that JQ-1/Bortezomib combination could be a promising treatment for MM and PEL, unveiling new molecular mechanisms underlying its cytotoxic effect and suggests that UPR and autophagy inhibition could be exploited to further potentiate the cytotoxicity of JQ-1/Bortezomib.
- || Review, Journal: Anticancer Activity of Diosgenin and Its Molecular Mechanism. (Pubmed Central) - Mar 21, 2023
Furthermore, in order to improve the biological activity and bioavailability of diosgenin, this review focuses on the development of diosgenin nano drug carriers, combined drugs and the diosgenin derivatives. However, further designed trials are needed to unravel the diosgenin's deficiencies in clinical application.
- | Preclinical, Journal: STAT3 signaling promotes cardiac injury by upregulating NCOA4-mediated ferritinophagy and ferroptosis in high-fat-diet fed mice. (Pubmed Central) - Mar 21, 2023
Based on these findings, we concluded that ferritinophagy-mediated ferroptosis was one of the critical mechanisms contributing to HFD-induced cardiac injury. The STAT3/NCOA4/FTH1 axis might be a novel therapeutic target for the treatment of HFD-induced cardiac injury.
- | KU-55933 / AstraZeneca
Journal: Ataxia-Telangiectasia Mutated Is Involved in Autolysosome Formation. (Pubmed Central) - Mar 21, 2023
In this study, we report that ATM inhibitors (KU-55933 and KU-60019) provoked accumulation of autophagosomes and p62 and restrained autolysosome formation...Repression of ATM expression using an siRNA inhibited autophagic flux at the autolysosome formation step and induced cell death under autophagy-inducing conditions. Taken together, our results suggest that ATM is involved in autolysosome formation and that the use of ATM inhibitors in cancer therapy may be expanded.
- | Journal: Rift Valley Fever Virus Nucleoprotein Triggers Autophagy to Dampen Antiviral Innate Immune Responses. (Pubmed Central) - Mar 21, 2023
RVFV NP-triggered autophagy strongly inhibited virus-induced expression of interferon-stimulated genes in infected macrophages but not in other tested cell types. Our study provides novel insights into the mechanisms of RVFV-triggered autophagy and highlights the potential of targeting autophagy flux to develop antivirals against this virus.
- | Journal: SlMYB72 affects pollen development by regulating autophagy in tomato. (Pubmed Central) - Mar 21, 2023
These results indicated SlMYB72 affects the tapetum degradation and pollen development by transcriptional activation of SlATG7 and autophagy in tomato anther. The study expands the understanding of the regulation of autophagy by SlMYB72, uncovers the critical role that autophagy plays in pollen development, and provides potential candidate genes for the production of male-sterility in plants.
- | Journal: Dual stimulus responsive borosilicate glass (BSG) scaffolds promote diabetic alveolar bone defectsrepair by modulating macrophage phenotype. (Pubmed Central) - Mar 21, 2023
Therefore, the addition of EGCG to BSG scaffold in diabetes allows for a more striking modulation of the macrophage phenotype in a timely manner. The altered macrophage phenotype reduces local inflammation and thus increases the ability to repair diabetic alveolar bone, showing promise for the treatment of alveolar defect in diabetic patients.
- | chloroquine phosphate / Generic mfg., sirolimus / Generic mfg.
Journal: Canine distemper virus N protein induces autophagy to facilitate viral replication. (Pubmed Central) - Mar 20, 2023
The altered macrophage phenotype reduces local inflammation and thus increases the ability to repair diabetic alveolar bone, showing promise for the treatment of alveolar defect in diabetic patients. This study for the first time revealed that CDV N protein induced complete autophagy to facilitate viral replication.
- | chloroquine phosphate / Generic mfg., MG132 / Jilin University, Dorothy M. Davis Heart and Lung Research Institute
Journal: Age-related cataract: GSTP1 ubiquitination and degradation by Parkin inhibits its anti-apoptosis in lens epithelial cells. (Pubmed Central) - Mar 20, 2023
This study for the first time revealed that CDV N protein induced complete autophagy to facilitate viral replication. Oxidative stress induces LECs apoptosis via Parkin-regulated degradation of GSTP1, which may provide potential targets for ARC therapy.
- | Journal: ETNPPL impairs autophagy through regulation of the ARG2-ROS signaling axis, contributing to palmitic acid-induced hepatic insulin resistance. (Pubmed Central) - Mar 20, 2023
Our study discloses that ETNPPL inhibiting autophagic flux mediates insulin resistance triggered by PA in hepatocytes via ARG2/ROS signaling cascade. Our findings provide novel insights into elucidating the pathogenesis of obesity-associated hepatic IR, suggesting that targeting ETNPPL might represent a potential approach for T2DM therapy.
- | Journal: The expanded ISG12 family in zebrafish: ISG12.1 suppresses virus replication via targeting viral phosphoprotein. (Pubmed Central) - Mar 20, 2023
Further, it was found that zebrafish ISG12.1 interacted with SVCV phosphoprotein (SVCV-P) and promoted SVCV-P degradation which could be attenuated by 3-MA and CQ (autophagy inhibitors). Our results indicate that zebrafish ISG12.1 restricts viral replication by targeting viral phosphoprotein for degradation.
- | cisplatin / Generic mfg.
Journal: Transcriptomic analysis reveals differential adaptation of colorectal cancer cells to low and acute doses of cisplatin. (Pubmed Central) - Mar 20, 2023
Overall, our study provides a holistic understanding of the distinct molecular signatures induced in CRC cells in response to differential cisplatin doses. These findings might facilitate the design of tailored therapy or appropriate drug dose for enhanced efficacy against CRCs.
- | chloroquine phosphate / Generic mfg., docetaxel / Generic mfg.
Journal: Self-assembled nanocomposites of carboxymethyl ?-dextran/protamine sulfate for enhanced chemotherapeutic drug sensitivity of triple-negative breast cancer by autophagy inhibition via a ternary collaborative strategy. (Pubmed Central) - Mar 20, 2023
The NPs exhibited remarkable considerable therapeutic effects for treating triple-negative breast cancer (TNBC) and good biosafety. Therefore, we established a novel multifunctional nanoplatform based on CMD and PS that enhances chemotherapeutic drug sensitivity through an autophagy inhibition strategy, providing new opportunities to overcome conventional drug resistance and enhance therapeutic efficiency against TNBC.
- | Journal: Lipopolysaccharide induces inflammatory microglial activation through CD147-mediated matrix metalloproteinase expression. (Pubmed Central) - Mar 20, 2023
At the same time, there was a certain interaction between MMPs and autophagy, which is shown that inhibiting the expression of MMPs could inhibit autophagy, whereas inhibiting autophagy could inhibit the expression of MMPs. Taken together, we provided the first evidence that CD147/MMPs can be involved in LPS-induced inflammatory activation of microglia through an autophagy-dependent manner.
- The Overexpression of Atg4B is a Novel Mechanism for Autophagy Inhibition in Preeclamptic Placentas. (Great Hall 3&4, Foyer Level) - Mar 20, 2023 - Abstract #SRI2023SRI_446;
We first found a similar finding in the placental tissues of PE/FGR. Thus, Atg4B could be a key molecule to inhibit autophagy in PE/FGR placentas, suggesting a brand-new mechanism for autophagy inhibition.
- Torin1 / InvivoGen
Autophagy Inhibition Induces Epithelial-to-Mesenchymal Transition in Fetal Membrane Chorion Trophoblast Cells. (Great Hall 3&4, Foyer Level) - Mar 20, 2023 - Abstract #SRI2023SRI_426;
In adverse pregnancies, inhibition of autophagy, and induction of EMT and inflammation in chorion destabilize membrane barrier functions. The mechanistic mediators of autophagy inhibition and the induction of EMT and the differential role it plays in the amnion and chorion needs further investigation.
- | chloroquine phosphate / Generic mfg.
Journal: Umbelliferone protects against cerebral ischemic injury through selective autophagy of mitochondria. (Pubmed Central) - Mar 19, 2023
Importantly, both the mitochondrial loss and reduction of SQSTM1 expression after UMB incubation can be reversed by autophagy inhibitor chloroquine and wortmannin, proving the mitophagy activation by UMB...Taken all, these results suggest that UMB protects against cerebral ischemic injury, both in vivo and in vitro, via promoting mitophagy without increasing the autophagic flux. UMB might serve as a potential leading compound for selectively activating mitophagy and the treatment of ischemic stroke.
- | GYY4137 / National University of Singapore
Journal: A Water-Soluble Hydrogen Sulfide Donor Suppresses the Growth of Hepatocellular Carcinoma via Inhibiting the AKT/GSK-3?/?-Catenin and TGF-?/Smad2/3 Signaling Pathways. (Pubmed Central) - Mar 17, 2023
In this study, compared with sodium hydrosulfide (NaHS, a fast HS-releasing donor) and morpholin-4-ium (4-methoxyphenyl)-morpholin-4-ylsulfanylidenesulfido-?5-phosphane (GYY4137, a slow HS-releasing donor), HA-ADT showed stronger inhibitory effect on the proliferation, migration, invasion, and cell cycle of human HCC cells...Therefore, HA-ADT can suppress the growth of HCC cells by blocking the AKT/GSK-3?/?-catenin and TGF-?/Smad2/3 signaling pathways. HA-ADT and its derivatives may be developed as promising antitumor drugs.
- | Journal: Sodium arsenite-induced cytotoxicity is regulated by BNIP3L/Nix-mediated endoplasmic reticulum stress responses and CCPG1-mediated endoplasmic reticulum-phagy. (Pubmed Central) - Mar 17, 2023
Nix downstream pathways were mitigated by Ca chelators. We demonstrate the critical roles of Nix and p62 in ER stress and ER-phagy in response to NaAR.
- | sirolimus / Generic mfg.
Preclinical, Journal: Role of Nuclear Factor of Activated T Cells-1 in Sepsis-induced Behavioral Deficits in Mice. (Pubmed Central) - Mar 16, 2023
We demonstrate the critical roles of Nix and p62 in ER stress and ER-phagy in response to NaAR. This study suggests that NFAT1 downregulation attenuates sepsis-induced behavioral deficits by inhibiting autophagy, microglia polarization, and neuroinflammation.
- | Journal: Cryptotanshinone inhibits oral squamous cell carcinoma through the autophagic pathway. (Pubmed Central) - Mar 16, 2023
Furthermore, we demonstrated that cryptotanshinone had a significant antitumor effect in a tumor xenograft model, and no damage to vital organs was observed. Our findings provide evidence that cryptotanshinone may be a novel therapeutic strategy for the treatment of OSCC.
- | methimazole / Generic mfg.
Journal: Hypothyroidism induces motor deficit via altered cerebellar HB-EGF/EGFR and autophagy. (Pubmed Central) - Mar 16, 2023
Additionally, 3-MA, HB-EGF and thyroxine attenuated the methimazole-induced diminution in riding time on rota-rod and grip strength for motor performance of rats. Overall, our study enlightens HB-EGF/EGFR-dependent autophagy mechanism as a key to cerebellar neuronal loss and functional impairments in developmental hypothyroidism, which may be inhibited by HB-EGF and 3-MA treatments, like thyroxine.
- | Journal: HIF-1?/Malat1/miR-141 Axis Activates Autophagy to Increase Proliferation, Migration, and Invasion in Triple-negative Breast Cancer. (Pubmed Central) - Mar 16, 2023
miR-141-3p could suppress autophagy and inhibit proliferation, migration, and invasion by targeting Malat1 in TNBC cells under hypoxia. The existence of the HIF-1?/Malat1/miR-141 axis plays a vital role in the development of TNBC and may be a target for the diagnosis and treatment of TNBC.
- | Journal: Hepatoprotective Effect of Myricetin following Lipopolysaccharide/D-Galactosamine: Involvement of Autophagy and Sirtuin 1. (Pubmed Central) - Mar 16, 2023
The existence of the HIF-1?/Malat1/miR-141 axis plays a vital role in the development of TNBC and may be a target for the diagnosis and treatment of TNBC. This study indicates the hepatoprotective potential of myricetin that can be ascribed to its down-regulation of oxidative, apoptotic, and inflammatory factors and upregulation of antioxidants besides its partial regulation of sirtuin 1 and autophagic pathway.
- | Journal: Design, synthesis, and discovery of Eudistomin Y derivatives as lysosome-targeted antiproliferation agents. (Pubmed Central) - Mar 15, 2023
Furthermore, the specific autophagy inhibitor 3-methyladenine significantly inhibited the H1k-triggered antiproliferation of cancer cells and the downregulation of CDK1 and cyclin B1. Overall, the lysosome is identified as the subcellular target of Eudistomin Y for the first time, and derivative H1k showed robust antiproliferative activity against MDA-MB-231
- | Journal: Copper(II) complex enhanced chemodynamic therapy through GSH depletion and autophagy flow blockade. (Pubmed Central) - Mar 15, 2023
Importantly, C2 significantly inhibited T24 tumor growth with 57.1% inhibition in a mouse xenograft model. C2 is a promising lead as a potential CDT anticancer agent.
- | Journal: CCDC115 inhibits autophagy-mediated degradation of YAP to promote cell proliferation. (Pubmed Central) - Mar 15, 2023
This interaction competes with STX17, thus inhibiting the fusion of autophagosomes with lysosomes. Hence, CCDC115 inhibits the autophagic degradation of yes-associated protein (YAP), thereby promoting cell proliferation in nutrient-restricted situation.
- | chloroquine phosphate / Generic mfg.
Journal: The role of FOXO1-mediated autophagy in the regulation of bone formation. (Pubmed Central) - Mar 15, 2023
Furthermore, inhibition of autophagy by chloroquine (CQ) could reverse favorable influences in bone formation induced by FOXO1 overexpression. Our findings confirmed that FOXO1 was an important regulator of bone formation and autophagy might be part of the underlying mechanisms, offering a significant avenue for the potential strategy in the treatment of bone-related disorders.
- | acetylcysteine solution / Generic mfg.
Preclinical, Journal, PARP Biomarker, IO biomarker: The in vitro and in vivo anticancer activities of Antrodia salmonea through inhibition of metastasis and induction of ROS-mediated apoptotic and autophagic cell death in human glioblastoma cells. (Pubmed Central) - Mar 15, 2023
Notably, the antioxidant N-acetylcysteine (NAC) inhibited AS-mediated ROS production and AS-induced apoptotic and autophagic cell death...AS reduced the tumor burden in GBM8401-xenografted nude mice and significantly modulated tumor xenografts by inducing anti-EMT, apoptosis, and autophagy. AS could be a potential antitumor agent in human glioblastoma treatment.
- | Journal: Innovative challenge for the inhibition of hepatocellular carcinoma progression by combined targeting of HSP90 and STAT3/HIF-1? signaling. (Pubmed Central) - Mar 15, 2023
Consequently, the use of 17-DMAG/NFXZD renders an inspirational perspective in managing HCC. However, further investigations are compulsory.
- | Journal: Salmonella Enteritidis RfbD enhances bacterial colonization and virulence through inhibiting autophagy. (Pubmed Central) - Mar 14, 2023
Mice infection experiments revealed that Z11?rfbD virulence was significantly reduced, and bacterial load was reduced in the liver and cecum in mice model, and LC3-II expression was significantly increased. These findings indicate an important role of Salmonella Enteritidis protein as a strategy to suppress autophagy and provides new ideas for manipulating autophagy as a novel strategy to treat infectious diseases.
- | Journal: Hydroxysafflor yellow a confers neuroprotection against acute traumatic brain injury by modulating neuronal autophagy to inhibit NLRP3 inflammasomes. (Pubmed Central) - Mar 14, 2023
These findings indicate an important role of Salmonella Enteritidis protein as a strategy to suppress autophagy and provides new ideas for manipulating autophagy as a novel strategy to treat infectious diseases. HSYA enhanced neuronal autophagy by triggering the AMPK/mTOR signalling pathway, leading to inhibition of the NLRP3 inflammasome to improve neurological recovery after TBI.
- | selisistat (SEN-196) / AOP Orphan Pharma
Preclinical, Journal: Bushen Wenyang Huayu Decoction inhibits autophagy by regulating the SIRT1-FoXO-1 pathway in endometriosis rats. (Pubmed Central) - Mar 14, 2023
BWHD inhibits autophagy by up-regulating SIRT1 and down-regulating FoXO-1 expression in EMs via the SIRT1-FoXO-1 signaling pathway. Therefore, it is a potential treatment for EMs.
- | Journal: DDX3-mediated miR-34 expression inhibits autophagy and HBV replication in hepatic cells. (Pubmed Central) - Mar 14, 2023
Overexpression of DDX3 in HBV expressing cells, downregulated expression of autophagy proteins while silencing of DDX3 reversed the results. These results led us to conclude that DDX3 upregulates miR-34 expression and thus inhibits autophagy in HBV expressing cells while HBx helps HBV evade DDX3 mediated inhibition by downregulating DDX3 expression in HBV infected cells.
- | Journal: Inhibition of autophagy reduces the rate of fluoride-induced LS8 apoptosis via regulating ATG5 and ATG7. (Pubmed Central) - Mar 14, 2023
More importantly, NaF-induced apoptosis can be reversed by inhibiting early stage of autophagy. In conclusion, our study shows that autophagy is closely related to dental fluorosis, and inhibition of autophagy, especially ATG5/7, reduces fluoride-induced cell death and apoptosis.
- | Journal: Adipose tissue-derived Muse cells promote autophagy and oxidative stress tolerance in human epidermal melanocytes. (Pubmed Central) - Mar 14, 2023
Treatment with the autophagy inhibitor, 3-methyladenine (3MA), partially counteracted the improvement of oxidative stress tolerance in melanocytes elicited by co-culture with Muse cells. Muse cells promote autophagy and oxidative stress tolerance of melanocytes.
- Autophagy & PIM1 kinase inhibition in breast cancer stem cells & bulk cancer cells attenuates breast cancer & metastasis (Section 1; Poster Board #1) - Mar 14, 2023 - Abstract #AACR2023AACR_8778;
Human tissue microarray results depicted high expression of NUMA1 & PIM1 in different breast cancer subtypes than non- tumor tissues. Our study demonstrated that inhibition of autophagy & PIM1 in bulk cancer cells & CSCs showed attenuation of tumor formation & metastasis, suggesting this combination treatment serves as an important therapeutic approach for treating breast cancer.
- narazaciclib (ON 123300) / Onconova
Differential targets engaged by narazaciclib in comparison to the approved CDK4/6 inhibitors contribute to enhanced inhibition of tumor cell growth (Section 9; Poster Board #16) - Mar 14, 2023 - Abstract #AACR2023AACR_8581;
P1
Combination of narazaciclib with autophagy inhibitors sensitized several breast cancer cells to cell death. Narazaciclib treatment may promote antitumor immunity by influencing the expression of various immune modulators in the tumor cells which needs to be further validated in preclinical animal models; and ultimately in the clinic.
- Ibrance (palbociclib) / Pfizer
The secretome produced by senescent gastric cancer cells can lead to different paracrine effects depending on the status of autophagy (Section 9; Poster Board #12) - Mar 14, 2023 - Abstract #AACR2023AACR_8578;
More specifically, the secretory phenotype of senescent gastric cancer cells seems to depend on the autophagy status.Materials and In order to determine the role of autophagy in the modulation of the SASP, cellular senescence was pharmacologically triggered in gastric cancer cell lines (AGS, MKN-45) through inhibition of CDK4/6 activity (0.5-1.0 ?M of Palbociclib for 48 and 96 hours), with or without the concomitant inhibition of autophagy by either genetic (knocking down ATG5) or pharmacologic (treatment with 0.5 ?M of Spautin-1) approaches...Our results suggest that autophagy modulates the expression of SASP components and, by so doing, affects the behavior of neighboring non-senescent cells. Interestingly, these effects were also influenced by the genetic status of gastric cancer cells.
- Targeting an autophagy regulator augments antitumor immunity and immunotherapy (Section 25; Poster Board #10) - Mar 14, 2023 - Abstract #AACR2023AACR_8549;
Furthermore, we found that inhibition of the regulator sensitizes syngeneic tumors to anti-PD1 therapy. Collectively, inhibition of this autophagy regulator augments antitumor immunity and immunotherapy via inducing MHC class I surface expression in cancer cells.
- Stellettin B induces apoptosis and autophagy in human bladder cancer RT112 cells (Section 19; Poster Board #6) - Mar 14, 2023 - Abstract #AACR2023AACR_8439;
Inhibition of autophagy by pharmacological inhibitors (3-MA and chloroquine) or ATG5 knockout protects stellettin B-induced apoptosis and cell viability suppression, indicating SP-2 induces autophagy to promotes cell death. Taken together, stellettin B may be a promising therapeutic agent for bladder cancer treatment.
- Iclusig (ponatinib) / Takeda, Otsuka, Incyte
Mechanisms by which Mito-lonidamine inhibits EGFR mutant lung cancer (Section 16; Poster Board #3) - Mar 14, 2023 - Abstract #AACR2023AACR_8379;
To discern cell death mechanisms, we evaluated FDA-approved inhibitors for autophagy (chloroquine, CQ), mitophagy/apoptosis (cyclosporin A, CsA) and necrosis (Ponatinib) in EGFR mutant cell lines using viability assays with Mito-LND treatment...These results begin to define the cancer inhibitory mechanisms of Mito-LND in EGFR mutant lung cancer cells which appear to differ from those observed in KRAS mutant lung cancer cells. Future directions include dissecting apoptotic and necrosis driven Mito-LND induced cell death using additional pharmacological inhibitors and genetic approaches.
- bortezomib / Generic mfg., carfilzomib / Generic mfg.
Proteasome inhibitors induce DNA damage and mitotic catastrophe in acute lymphoblastic leukemia via autophagy-mediated degradation of WEE1 (Section 18; Poster Board #1) - Mar 14, 2023 - Abstract #AACR2023AACR_8348;
Moreover, carfilzomib trigger autophagy-mediated degradation of WEE1 in ALL via induction of ER-stress. The findings provide mechanistic insights of carfilzomib in ALL and rationalize the introduction of novel approach of combination treatment of carfilzomib with other DNA damaging agents.
- mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, temuterkib (LY3214996) / Eli Lilly, Mektovi (binimetinib) / Ono Pharma, Pierre Fabre, Pfizer
Improving the efficacy of dual ERK-MAPK and autophagy inhibition as a therapeutic strategy for pancreatic ductal adenocarcinoma (Section 12; Poster Board #24) - Mar 14, 2023 - Abstract #AACR2023AACR_7607;
P1, P2
These findings provided rationale for our initiation of Phase I/II clinical trials evaluating the combination of MEKi (binimetinib; NCT04132505) or ERKi (LY3214996; NCT04386057) with HCQ in PDAC...Importantly, when we inhibited MEK, with the clinical stage MEKi mirdametinib, and PIKfyve (with apilimod) together, we observed decreased MEKi-induced autophagic flux and synergistic impairment of PDAC cell proliferation...Furthermore, combining ERK-MAPK inhibition with vertical inhibition of autophagy improves the in vitro efficacy of this treatment strategy. Ongoing studies are aimed at delineating the mechanism underlying the synergy observed with anti-autophagy inhibitor combinations and further validation in more advanced preclinical models of PDAC.
- Qinlock (ripretinib) / Deciphera, DCC-3116 / Deciphera
DCC-3116, a first-in-class selective ULK1/2 inhibitor of autophagy, in combination with the KIT inhibitor ripretinib induces complete regressions in GIST preclinical models (Section 13; Poster Board #15) - Mar 14, 2023 - Abstract #AACR2023AACR_7218;
P1/2
These data demonstrate preclinically that, like other receptor tyrosine kinase inhibitors1, ripretinib activates ULK1/2-mediated autophagy as an ASR resistance mechanism which is inhibited by DCC-3116, providing the rationale to study the combination of DCC-3116 with ripretinib in GIST patients. DCC-3116 is currently in a Phase 1 clinical trial in patients with advanced solid tumors (NCT04892017).
- defactinib (VS-6063) / Verastem
DIRAS3 suppresses ovarian cancer cell growth through the inhibition of fibronectin-mediated FAK/AKT signaling (Section 6; Poster Board #23) - Mar 14, 2023 - Abstract #AACR2023AACR_5455;
Pharmacologic inhibition of FAK using defactinib, enhanced DIRAS3-induced autophagy, inducing cell death in ovarian cancer cells in the presence of FN. Together, our data demonstrate that factors such as FN, block DIRAS3-induced autophagic cell death, contributing to the survival of ovarian cancer cells.
- Loss of TC-PTP in keratinocytes leads to increased UVB-induced autophagy (Section 8; Poster Board #14) - Mar 14, 2023 - Abstract #AACR2023AACR_5220;
Pretreatment of CQ before UVB irradiation in TC-PTP KO keratinocytes significantly reduced cell viability compared to untreated TC-PTP KO keratinocytes. These results suggest that TC-PTP protects keratinocytes from UVB-induced damage by negatively regulating autophagy signaling.