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67 Companies | 59 Products |
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344 Diseases | |
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- | Herceptin (trastuzumab) / Roche
Journal: Cullin7 Enhances Resistance to Trastuzumab Therapy in Her2 Positive Breast Cancer via Degrading IRS-1 and Downregulating IGFBP-3 to Activate the PI3K/AKT Pathway. (Pubmed Central) - May 23, 2020
Overexpression of Cullin 7 in Her2-amplified breast cancer tissues has clinical implications because it positively correlates with shorter disease-free survival (DFS) and inadequate response to trastuzumab. Thus, our results suggest a critical role for Cullin7 in response to trastuzumab, which has significant implications for selection of the optimal therapeutic strategy for Her2 positive breast cancers.
- || Focused on PI3K-AKT signalling in HR+/HER2-. #ESMOBreast20 #OncoAlert @myESMO (Twitter) - May 23, 2020
- || #BiomedNews on #PI3K in #cancer and #development by @RalitsaMadsen from @uclcancer (Twitter) - May 23, 2020
- | Journal: FNDC3B, Targeted by miR-125a-5p and miR-217, Promotes the Proliferation and Invasion of Colorectal Cancer Cells via PI3K/mTOR Signaling. (Pubmed Central) - May 22, 2020
Generally, our findings demonstrated that FNDC3B facilitated cell proliferation and invasion via PI3K/mTOR signaling, and further promoted CRC progression. The novel miR-125a-5p/FNDC3B and miR-217/FNDC3B axes might be new targets for CRC prognosis and therapy.
- | Journal: Long noncoding RNA MALAT1 inhibits the apoptosis and autophagy of hepatocellular carcinoma cell by targeting the microRNA-146a/PI3K/Akt/mTOR axis. (Pubmed Central) - May 22, 2020
miR-146a directly targeted the 3'-untranslated region of PI3K, and PI3K protein level was clearly decreased upon miR-146a mimic transfection. MALAT1 may modulate HCC cell proliferation, apoptosis, and autophagy via sponging miR-146a, which regulates HCC progression.
- | Journal: IR-A/IGF-1R-mediated signals promote epithelial-mesenchymal transition of endometrial carcinoma cells by activating PI3K/AKT and ERK pathways. (Pubmed Central) - May 21, 2020
IR-A and IGF-1R-mediated signals, by activating PI3K/AKT and ERK pathways, can induce multiple malignant phenotypes of EC cells. Therefore, targeting IR-A or IGF-1R may provide therapeutic benefits for EC.
- | Journal: Activation of prostaglandin EP4 receptor attenuates the induction of cyclooxygenase-2 expression by EP2 receptor activation in human amnion fibroblasts: implications for parturition. (Pubmed Central) - May 21, 2020
We conclude that EP2 and EP4 receptors play different roles in the regulation of COX-2 expression in human amnion fibroblasts. EP2 is the dominant PGE2 receptor mediating the induction of COX-2 at parturition, which can be attenuated by simultaneous activation of PI3K coupled to the EP4 receptor.-Lu, J.-W., Wang, W.-S., Zhou, Q., Gan, X.-W., Myatt, L., Sun, K. Activation of prostaglandin EP4 receptor attenuates the induction of cyclooxygenase-2 expression by EP2 receptor activation in human amnion fibroblasts: implications for parturition.
- | cisplatin / Generic mfg.
Journal: The PAX6-ZEB2 axis promotes metastasis and cisplatin resistance in non-small cell lung cancer through PI3K/AKT signaling. (Pubmed Central) - May 21, 2020
Moreover, p-PI3K and p-AKT were significantly enhanced by PAX6, which was reversed by the addition of the PI3K-AKT inhibitor, LY294002. These data suggest that PAX6 can mediate E-cadherin downregulation through the PI3K/AKT signaling pathway by directly binding the promoter region of ZEB2, thereby mediating cell migration, stem cell transformation, and cisplatin resistance; and ultimately, affecting survival in NSCLC patients.
- | Journal: The RAC2-PI3K axis regulates human NK cell maturation and function. (Pubmed Central) - May 21, 2020
These data suggest that PAX6 can mediate E-cadherin downregulation through the PI3K/AKT signaling pathway by directly binding the promoter region of ZEB2, thereby mediating cell migration, stem cell transformation, and cisplatin resistance; and ultimately, affecting survival in NSCLC patients. No abstract available
- sirolimus / Generic mfg.
[VIRTUAL] Platelet specific Ablation of Mtor Regulates Platelet Aggregation and in vivo Thrombosis Through Rap1b Mediated Integrin Alphaiibbeta3 Activation () - May 20, 2020 - Abstract #ATVBPVDGPM2020ATVB_PVD_GPM_91;
In both models, platelet mTOR-deficiency resulted in decreased thrombosis. Our data demonstrate that mTOR regulates integrin αIIbβ3-activation and in vivo thrombosis through Rap1b.
- | Preclinical, Journal: Inhibition of PI3K/AKT/mTOR signaling pathway promotes autophagy and relieves hyperalgesia in diabetic rats. (Pubmed Central) - May 20, 2020
Therefore, we conclude that activation of the PI3K/AKT/mTOR pathway and impaired autophagy may be key factors that cause PDN. Inhibition of the PI3K/AKT/mTOR pathway could promote autophagy activity and alleviate PDN.
- NETO2 PROMOTES ESOPHAGEAL CANCER PROGRESSION BY INDUCING PROLIFERATION AND METASTASIS VIA PI3K/AKT AND ERK PATHWAYS () - May 19, 2020 - Abstract #SSAT2020SSAT_112;
Therefore, our data suggest that Nrf2 was a critical downstream event responsible for triggering the PI3K/AKT and ERK signaling pathways and plays a crucial role in NETO2-mediated tumorigenesis. Taken together, NETO2 acts as an oncogene and might serve as a novel therapeutic target or prognostic biomarker in ESCC patients.
- || Biomarker, Clinical, Journal, IO Biomarker: Genetic mutations in chronic lymphocytic leukemia: impact on clinical treatment. (Pubmed Central) - May 19, 2020
In this scenario, predictive biomarkers can assist physicians in optimizing treatment tailoring. Furthermore, treatment-emergent mutations leading to drug resistance are discovered in the majority of patients treated with BTK inhibitors and BCL2 inhibitors, which could be switched to an alternative option.
- | Journal: PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression. (Pubmed Central) - May 19, 2020
Thus, SGK1 regulates the chromatin landscape and ER-dependent transcription via the direct phosphorylation of KMT2D. These findings reveal an ER-SGK1-KMT2D signaling circuit aimed to attenuate ER response through a role for SGK1 to program chromatin and ER transcriptional output.
- | Journal: Vitamin D attenuates lipopolysaccharide-induced inflammatory response in endothelial cells through inhibition of PI3K/Akt/NF-κB signaling pathway. (Pubmed Central) - May 19, 2020
Blocking NF-κB signaling blunted the suppression effect of 1,25(OH)₂D₃ on IκBα phosphorylation, NF-κB accumulation in the nucleus and COX-2 expression. These results indicate that 1,25(OH)₂D₃ suppresses inflammatory response in LPS-induced HUVECs through PI3K/Akt/NF-κB signaling pathway.
- | Journal: Mercury induces nuclear estrogen receptors to act as vasoconstrictors promoting endothelial denudation via the PI3K/Akt signaling pathway. (Pubmed Central) - May 19, 2020
Mercury exposure also induced nuclear estrogen receptors (ERα, ERβ) to act as vasoconstrictors. Our findings suggest that mercury might increase the chances of developing cardiovascular diseases in females and should be considered an important environmental risk factor.
- | Journal: Elevated luteinizing hormone contributes to atherosclerosis formation by inhibiting nitric oxide synthesis via PI3K/Akt pathway. (Pubmed Central) - May 19, 2020
Elevated LH promotes atherosclerosis formation in OVX ApoE female mice. This effect may be mediated by inhibiting endothelial NO synthesis via PI3K/Akt signaling pathway.
- | Journal: PI3K/AKT inhibitors aggravate death receptor-mediated hepatocyte apoptosis and liver injury. (Pubmed Central) - May 19, 2020
Conversely, cotreatment with the AKT specific activator SC79 reversed these effects. Taken together, these findings suggest that PI3K or AKT inhibitors may render hepatocytes hypersensitive to Fas- or TNFα-induced apoptosis and liver injury.
- || Clinical, Journal: PI3K (Phosphatidylinositol 3-Kinase) Activation and Endothelial Cell Proliferation in Patients with Hemorrhagic Hereditary Telangiectasia Type 1. (Pubmed Central) - May 19, 2020
In conclusion, we detected an increase in EC proliferation linked to overactivation of the PI3K pathway in cutaneous telangiectasia biopsies from HHT1 patients. Our results suggest that PI3K inhibitors could be used as novel therapeutic agents for HHT.
- | Journal: Inhibition of Nasopharyngeal Carcinoma by Beta-Lapachone Occurs by Targeting the Mammalian Target of Rapamycin (mTOR)/PI3K/AKT Pathway, Reactive Oxygen Species (ROS) Production, and Autophagy Induction. (Pubmed Central) - May 19, 2020
The beta-lapachone-triggered autophagy was also associated with increased protein levels of LC3 II and decreased levels of p62. CONCLUSIONS The findings of this study suggest that beta-lapachone inhibits the growth of nasopharyngeal cancer cells by promoting autophagy, and it may be useful in cancer drug discovery paradigms.
- | doxorubicin hydrochloride / Generic mfg.
Journal: Sodium azulene sulfonate reverses multidrug resistance in K562/A02 cells. (Pubmed Central) - May 19, 2020
Sodium azulene sulfonate (SAS) was used to reverse the multidrug resistance of human leukemia adriamycin-resistant strain K562/A02, and the underlying mechanism was investigated...This contributed to the reversal of drug resistance.SAS effectively reverses multidrug resistance in vitro by inhibiting the function of p-gp in K562/A02 cells, through a mechanism involving downregulation of the P13K/Akt signaling pathway. Therefore, SAS may be a potential candidate drug for reversal of MDR.
- | sirolimus / Generic mfg., doxorubicin hydrochloride / Generic mfg.
Journal: Resistance of THP-1 Leukemia Cells Infected with Cytomegalovirus to Anti-tumor Antibiotic Doxorubicin and Restoration of the Sensitivity by Inhibitors of the PI3K/AKT/mTOR Molecular Pathway. (Pubmed Central) - May 19, 2020
Rapamycin inhibited the expression of the HCMV protein IE1-p72 and increased sensitivity to DOX. Molecular targets for the creation of new drugs for the treatment of leukemia in patients infected with HCMV were determined.
- | donepezil / Generic mfg.
Preclinical, Journal: Qingxin Kaiqiao Recipe Improves Cognitive Performance, Inhibits Apoptosis, and Reduces Pathological Deposits in APP/PS1 Double Transgenic Mice via the PI3K/Akt Pathway. (Pubmed Central) - May 19, 2020
APP/PS1 double transgenic mice were randomly divided into a model, donepezil-treated, or QKR-treated group (L-QKR: 4.75 mg/kg/d, M-QKR: 9.5 mg/kg/d, and H-QKR: 19 mg/kg/d, respectively)...In addition, the number of TUNEL-positive cells decreased after treatment using QKR. The current study proved that QKR, especially at the high dose tested, exerted a protective effect on improving learning and memory, inhibiting apoptosis, and reducing the process of pathological degeneration in the hippocampus of AD mice.
- [VIRTUAL] Oral Consumption of a PI3K P110a Inhibitor Perturbs Glucose Homeostasis without Affecting the Physical or Cognitive Function of Adult Mice () - May 18, 2020 - Abstract #ADA2020ADA_1575;
Collectively, these data indicate that short-term pharmacological inhibition of PI3K p110α alters glucose homeostasis, but has only mild effect with respect to the physiological stimulus of a meal, and without deterioration of physical or cognitive function in adult mice. This indicates BYL-719 is safely tolerated in adult mice, and longer-term study is warranted to test the efficacy of BYL-719 in prolonging lifelong health in an aged population.
- | Journal: Liraglutide Promotes the Osteogenic Differentiation in MC3T3-E1 Cells Via Regulating the Expression of Smad2/3 Through PI3K/Akt and Wnt/β-Catenin Pathways. (Pubmed Central) - May 18, 2020
Liraglutide facilitated the osteogenic differentiation via the regulation of Smad2/3 via PI3K/AKT and Wnt/β-catenin pathways. These data revealed a new mechanism of Liraglutide inducing osteogenic differentiation and provided theory evidence to maintain normal bone metabolism during diabetes therapy.
- | Journal: Low expression of PDK1 inhibits renal cell carcinoma cell proliferation, migration, invasion and epithelial mesenchymal transition through inhibition of the PI3K-PDK1-Akt pathway. (Pubmed Central) - May 18, 2020
While a notable observation was made highlighting that the PI3K-PDK1-Akt pathway antagonized the effect of PDK1 silencing. Taken together, the key observations of this study provide evidence suggesting that high expressions of PDK1 are found in RCC, while highlighting that silencing PDK1 could inhibit RCC cell proliferation, migration, invasion and EMT by repressing the PI3K-PDK1-Akt pathway.
- || quercetin (LY294002) / Eli Lilly
Clinical, Journal: Microtia patients: Auricular chondrocyte ECM is promoted by CGF through IGF-1 activation of the IGF-1R/PI3K/AKT pathway. (Pubmed Central) - May 18, 2020
Taken together, the key observations of this study provide evidence suggesting that high expressions of PDK1 are found in RCC, while highlighting that silencing PDK1 could inhibit RCC cell proliferation, migration, invasion and EMT by repressing the PI3K-PDK1-Akt pathway. CGF-released IGF-1 stimulates the synthesis of the auricular chondrocyte ECM via the IGF-1R/PI3K/AKT signaling pathway.
- ||| Copiktra (duvelisib) / Secura Bio, Yakult Honsha
Enrollment open, HEOR, Real-world evidence, Real-world: Observational Trial of Real-World Treatment Utilization and Effectiveness of PI3K-inhibitors in CLL/SLL and FL (clinicaltrials.gov) - May 17, 2020
P=N/A, N=200, Recruiting, Sponsor: Verastem, Inc.
CGF-released IGF-1 stimulates the synthesis of the auricular chondrocyte ECM via the IGF-1R/PI3K/AKT signaling pathway. Not yet recruiting --> Recruiting
- | Biomarker, Journal: CD73 promotes hepatocellular carcinoma progression and metastasis via activating PI3K/AKT signaling by inducing Rap1-mediated membrane localization of P110β and predicts poor prognosis. (Pubmed Central) - May 17, 2020
CD73 promotes progression and metastasis through activating PI3K/AKT signaling, indicating a novel prognostic biomarker for HCC. Our data demonstrate the importance of CD73 in HCC in addition to its immunosuppressive functions and revealed that co-targeting CD73 and A2AR strategy may be a promising novel therapeutic strategy for future HCC management.
- | Journal: Overexpression of lncRNA Gm2691 attenuates apoptosis and inflammatory response after myocardial infarction through PI3K/Akt signaling pathway. (Pubmed Central) - May 17, 2020
Western blot analysis revealed that lncRNA Gm2691 decreased Akt and ERK1/2 activities, suggesting that lncRNA Gm2691 may functioned through Akt signaling pathway. We verified the function and mechanism of lncRNA Gm2691 and provide evidence that lncRNA Gm2691 may play important role in ischemic reperfusion injury, and understanding the precise role of Gm2691 will undoubtedly shed new light on the clinical treatment.
- | Journal: Astaxanthin inhibits hallmarks of cancer by targeting the PI3K/NF-κΒ/STAT3 signalling axis in oral squamous cell carcinoma models. (Pubmed Central) - May 17, 2020
We suggest that AXT prevents cell proliferation, apoptosis evasion, invasion and angiogenesis by intercepting the crosstalk between the PI3K/Akt, NF-κB and STAT-3 signalling circuits both in vitro and in vivo. Astaxanthin that abrogates the PI3K/Akt signalling axis, a central hub that orchestrates acquisition of cancer hallmarks is a promising candidate for anticancer drug development.
- | Journal: Up-regulation of IGF2BP2 by multiple mechanisms in pancreatic cancer promotes cancer proliferation by activating the PI3K/Akt signaling pathway. (Pubmed Central) - May 17, 2020
We comprehensively reveal the oncogenic role of IGF2BP2 in pancreatic cancer carcinogenesis and confirm that genomic amplification and the silencing of miR-141 contribute to its activation. Our findings highlight that IGF2BP2 may be a promising molecular target for the treatment of pancreatic cancer.
- | Journal: Highly-expressed micoRNA-21 in adipose derived stem cell exosomes can enhance the migration and proliferation of the HaCaT cells by increasing the MMP-9 expression through the PI3K/AKT pathway. (Pubmed Central) - May 17, 2020
We have found a reliable evidence that these two factors can act on HaCaT cells by influencing MMP-2 and TIMP-1 protein expression through the PI3K/AKT signal pathway. These results may provide a provide potential perspectives on improving the wound healing.
- sirolimus / Generic mfg., paclitaxel / Generic mfg.
Longitudinal proteomic assessment of patient with metastatic apocrine adenocarcinoma reveals evolutionary selection for androgen-receptor-dependence and therapeutic response (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_89;
The patient underwent craniotomy, began paclitaxel therapy, and then RETB declined to 35,623 mm3...The patient then received the PI3K inhibitor taselisib; however, after an initial decrease, RETB rose to 31,208 mm3.At this point, the patient began bicalutamide therapy...After 9 months of bicalutamide, enzalutamide and leuprolide were administered for 7 months (final RETB = 1,555 mm3)...We identified the phenotypic evolution of androgen-driven growth of apocrine adenocarcinoma after cytotoxic and PI3K-mTOR inhibitor therapy. Protein-based diagnostics revealed an effective treatment strategy in late metastatic disease that was not indicated by NGS testing.
- Landscape of PI3K-AKT-mTOR pathway gene alterations in early breast cancer: Implications for targeted therapeutics (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_882;
Our study identified mutational patterns in the PI3K-AKT-mTOR pathway among the Chinese patients with various molecular subtypes of early breast cancer. Patients with multiple PIK3CA mutations have a significantly worse prognosis than patients with a single mutation and those without mutations, suggesting that inhibitors designed to effectively target PIK3CA could contribute in improving the prognosis of these patients.
- Faslodex (fulvestrant) / AstraZeneca
Discovery of ZN-c5, a novel potent and oral selective estrogen receptor degrader (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_845;
The PK profile of ZN-c5 in breast cancer patients indicates that Zn-c5 has greater than 5-fold exposure than fulvestrant. We believe that the high exposure of ZN-c5 coupled with its potency and degradative properties could therapeutic benefit estrogen receptor positive breast cancer patients.
- quercetin (LY294002) / Eli Lilly
Novel approach for automated sequential immunoassay for quantitation and characterization of PI3K-Akt pathway proteins (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_766;
Akt is a target for specific inhibition and recently, a number of small molecules have been developed to improve the pharmacologic properties of known inhibitors like wortmannin and LY294002...This approach enables normalization of phosphorylation levels and/or target abundance in cell line or tissue samples, correcting for change in protein content due to treatment, loading, and/or other systematic errors. These results present the utility of the Multiple Detection Approach to quickly characterize and quantify proteins involved in signaling pathways targeted during development of cancer therapies.
- Targeting of AKT pathway inhibit high-risk neuroblastoma growth (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_500;
Overall, these data highlight that: a) AKT signaling pathway is implicated in NB growth, b) PI3K and PDK1 upstream of the AKT are important regulators of NB proliferation, and c) direct targeting of these regulators is a novel therapeutic approach to high-risk NB. We will further explore these strategies and combine them with current therapies to develop effective therapeutic approaches for NB patients.
- paxalisib (GDC-0084) / Kazia
Phase 2 study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K / mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_444;
P1, P2
Nine patients were recruited and an MTD of 60mg was determined. DLTs were hyperglycemia and oral mucositis, with toxicity and patterns of AEs consistent with prior experience and other PI3K-targeting agents.
- carboplatin / Generic mfg., buparlisib (BKM120) / Novartis, Adlai Nortye
Assays of conventional chemotherapeutics and targeted drugs for ovarian cancer using patient derived models (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_4082;
Several PI3K inhibitors were assayed on PDTCs of this PDX line harboring the PIK3R1W624R. Buparlisib (a Pan Class I PI3Ki) showed the ability to block proliferation of the PDTCs and the growth of the relevant PDXs in vivo.Altogether these data show that Patient Derived models are invaluable tools to unveil actionable pathways for the treatment of advanced/metastatic HGS-EOC.
- CA-102N / Holy Stone Healthcare
CA102N suppresses the growth of mouse colon cancer by inhibition of PI3K pathway and immune modulation (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_4033;
Additionally, the protein expression of pAkt and pS6 in CA102N (200 mg/kg) treated tumor tissues were significantly down-regulated by more than 50% compared to that of control group, while CA102N (50 mg/kg) treatment only slightly altered the abundance of these proteins, suggesting antitumor activity of CA102N in different doses can potentially be mediated by differential mechanisms. Together, these findings suggest that the lower dose of CA102N exerts antitumor activity in mouse colon tumor model by immune modulation whereas the antitumor activity of the higher dose of CA102N might be mediated through inhibition of PI3kinase pathway on tumor tissues.
- imatinib / Generic mfg.
Influence of PI3K/AKT pathway on imatinib mesylate treatment outcome in chronic myeloid leukemia patients (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_3992;
However, with respect to the clinical phase and imatinib response, none of the genes showed significant differences except for PTEN, which was significantly downregulated in advanced phase (p<0.042) and in cases with poor imatinib response. Overall, these results indicate a critical role for PI3K pathway in CML and its maintenance.
- Xalkori (crizotinib) / Pfizer, bemcentinib (BGB324) / BerGenBio
Identifying the role of AXL in fusion kinase inhibitor resistant non-small cell lung cancer (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_3897;
In a RET inhibitor resistant model expression of both AXL and EGFR are elevated and the receptors interact, which can be disrupted upon EGF stimulation, to drive resistance. Collectively, we show that AXL upregulation is a common marker of TKI resistance among ALK, ROS1, and RET fusion kinase driven lung adenocarcinoma models, and provide rationale for AXL as a clinical target for combination therapy to overcome drug resistance.
- HMPL-689 - Chi / Med
A phase I study of HMPL-689, a small molecule selective inhibitor of phosphoinositide 3-kinase-delta, inpatients with relapsed or refractory lymphoma (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_3788;
Ongoing global studies are still open and enrolling patients with R/R lymphoma. Validated data / results from this study will be made available at the end of dose escalation and or at the conclusion of dose expansion stage.
- Elucidating the role of PI3K lipid effectors in BRAF mutant melanoma (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_3771;
However, it has not been shown if constitutively active AKT alone is able to substitute for this effect. Further research will elucidate the role of AKT in the initiating stages of melanoma and provide a more thorough understanding of the PI3K/AKT signaling pathway in promoting BRAF mutant melanomagnesis.
- paxalisib (GDC-0084) / Kazia
A dose escalation phase I study of concurrent GDC-0084 with radiation therapy for patients with solid tumor brain metastases or leptomeningeal metastases harboring PI3K pathway mutations (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_3660;
P1
The starting dose of GDC-0084 is 45mg daily and a maximum of 24 patients will be required to establish the maximum-tolerated dose (MTD). Once the MTD is determined, an expansion cohort of 12 patients will be treated.
- prexasertib (LY2606368) / Eli Lilly, Pfizer, SOM Biotech, Ewha Womans University, samotolisib (LY3023414) / Eli Lilly
Combined inhibition of checkpoint kinase 1 (CHK1) and phosphoinositide 3-kinase (PI3K) pathways induces greater replication stress and DNA damage in high-grade serous ovarian cancer (HGSOC) (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_3549;
We thus conducted a high throughput drug combination screening of a CHK1i, prexasertib (Prex) with 1,912 drugs in HGSOC cell lines (BRCA wild-type [BRCAwt: OVCAR5 and OVCAR8] and BRCA2 mutant [BRCA2m: PEO1])...We confirmed the combination of Prex and a dual PI3K/mTOR inhibitor LY3023414 (LY302) yielded synergistic cytotoxicity (combination index<1) in a panel of HGSOC cell lines (OVCAR3, OVCAR5, OVCAR8, OV90 and PEO4 [all BRCA-proficient] and PEO1) by XTT and colony formation assays...Supporting this notion, Prex+LY302 augmented RS as evidenced by increased phospho-RPA+/γH2AX+ populations compared with Prex (increased 37% and 38%, respectively; P<0.05) or LY302 (increased 80% and 79%, respectively; P<0.001). Overall, our results suggest that dual inhibition of CHK1 and PI3K pathways results in greater RS, DNA damage and subsequent cell death in HGSOC cells independent of BRCA mutation status.
- Resistance to anti-HER2 therapy in HER2+ breast cancer is mediated by genomic alterations that switch pathway dependence from PI3K/AKT to RAS/MAPK (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_3130;
Unexpectedly, resistant models exhibited diminished dependence on AKT (MK2206 IC50 increase from 200 nM to 4500 nM) and were sensitized to MEK/ERK inhibition (trametinib IC50 decrease from 740 nM to 13 nM and SCH772984 from 2900 nM to 250 nM)...Finally, using lentiviral CRISPR/Cas9, we knocked out NF1 in a HER2+ patient derived xenograft model and again found that this alteration promoted profound MEK dependence in vivo. Overall, these data suggest that MAPK-activating mutations constitute an important potential mode of acquired resistance to HER2-targeted therapies and demonstrate the potential utility of MEK/ERK targeted therapies for a subset of anti-HER2 therapy resistant HER2+ breast cancers.
- pictilisib (GDC-0941) / Roche, Faslodex (fulvestrant) / AstraZeneca
Kinome rewiring upon acquisition of resistance to PI3K inhibitors in ER+ breast cancer (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_3129;
Previous work showed that PARD3 is central for the formation of tight junctions. These data collectively suggest a dynamic role of kinase-substrate interactions involved in resistance to combined anti-estrogen/PI3Ki treatment, including filamentation actin formation and stabilization, as well as the deregulation of tight junction formation.
- Src-Met signaling confers apoptosis resistance to EGFR and PI3K co-targeting independently of AKT and ERK pathway activation in head and neck cancer (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_3128;
Some resistant cell lines express a high level of p-Met as a downstream target of SFK, which confers resistance of these cells to EGFR and PI3K co-targeting. Finally, Met confers apoptosis resistance independently of AKT and ERK pathway activation.