pictilisib (GDC-0941)

We identified a class I PI3K inhibitor, pictilisib and p21 activated kinase (PAK) inhibitor, PF-3758309 as the top combination due to high synergy in cell viability assays. The inhibitor combination promoted cell cycle arrest and apoptosis in mouse merlin-deficient Schwann (MD-SCs) cells and cell cycle arrest in human MD-SCs. This study identifies the PI3K and PAK pathways as potential targets for combination drug treatment of NF2-related schwannomatosis.

Importantly, the PI3K-inhibitor GDC0941 fully mimicked the effects of fluoxetine. Collectively, our findings demonstrate that fluoxetine exerts potent anti-inflammatory effects, and suppresses the release of the endogenous itch mediator endothelins in human keratinocytes, most likely via indirect inhibition of PI3K. Thus, clinical studies are encouraged to explore whether the currently reported beneficial effects translate in vivo following its topical administration in inflammatory and pruritic dermatoses.

A series of in vitro and in vivo experiments showed that XIN-10 has superior antiproliferative activity compared with the positive drug GDC-0941. Meanwhile, through the results of protein blotting and PCR experiments, we concluded that XIN-10 can block the activation of the downstream pathway of mTOR by inhibiting the phosphorylation of AKT(S473) as well as having significant inhibitory effects on the gene exons of PI3K and mTOR. These results indicate that XIN-10 is a highly potent inhibitor with low toxicity and has a strong potential to be developed as a novel PI3Kα/mTOR dual inhibitor candidate for the treatment of positive breast cancer.

A fast and reliable QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) method for pre-processing combined with Ultra - high performance liquid chromatography - tandem mass spectrometry (UHPLC-MS/MS) was established for the analysis of five mammalian rapamycin target protein (mTOR) inhibitors (vistusertib, AZD8055, pictilisib, everolimus, temsirolimus)in human plasma. This method showed a high accuracy with high recovery rate and excellent stability. This method is fast, accurate and reliable, suitable for quantitative detection of mTOR inhibitors in human plasma.

In patient-derived models, erdafitinib was synergistic with pictilisib in the presence of PIK3CA E545K, whereas erdafitinib-gefitinib combination was able to overcome bypass resistance mediated by EGFR activation. Eleven (52%) patients harbored alterations in the PI3K-mTOR pathway (n = 5 TSC1/2, n = 5 PIK3CA, n = 1 NF2, n = 1 PTEN). In patient-derived models, erdafitinib was synergic with pictilisib in the presence of PIK3CA E545K, while erdafitinib-gefitinib combination was able to overcome bypass resistance mediated by EGFR activation.

In the xenograft mouse model, the combination of Pictilisib and GPC-1 knockdown exhibited synergy. These findings suggest that GPC-1 represents a promising target to augment chemosensitivity in esophageal adenocarcinoma.

These results demonstrate that pictilisib used as a single agent induces acute resistance, partly through FOXO1 inhibition. Therefore, overcoming PI3Ki single-agent adaptive resistance by rational design of FOXO1 and PI3K inhibitor combinations could significantly enhance the therapeutic efficacy of PI3K-targeting drugs in MCA cells.

In vitro, blocking the PI3K pathway with GDC-0941 (pictilisib), or BYL719 (alpelisib), prevented AKT pathway hyperactivation and enhanced the efficacy of trametinib in a synergistic manner. We confirmed our findings in a syngeneic murine head and neck cancer cell line in vitro and in vivo. Taken together, our findings show that trametinib treatment induces hyperactivation of EGFR/PI3K/AKT; thus, blocking of the EGFR/PI3K pathway is required to improve trametinib efficacy in HNSCC.

In the chemotherapy drug sensitivity analysis, we found that the high Risk Score group might be more suitable for treatment with PI3K inhibitors Taselisib and Pictilisib. In addition, we found that patients in the low-risk group responded better to immunotherapy. Risk Score of 9-gene composition of PCD signature possesses promising clinical potential in OV prognosis, immunotherapy, immune microenvironment activity, and chemotherapeutic drug selection, and our study provides the basis for an in-depth investigation of the PCD mechanism in OV.

In a selection of 166 compounds we showed that inhibitors of ATR and WEE1 were cytotoxic against a panel of OCCC cell lines. These two drugs are already in other clinical trials, making them ideal candidates for treatment of OCCC.

Conversely, one study using telapristone acetate showed Ki67d only in premenopausal pts. Higher body mass index (BMI) was reported to be associated with Ki67d, in one of the studies together with metformin...Higher Ki67d was reported when pictilisib or enzalutamide were added to NET in luminal B or luminal A tumors, respectively...The effect of this mutation was reverted in these studies by the addition of targeted therapy to NET (pictilisib, everolimus, or lapatinib). Conclusions We summarize baseline characteristics associated with Ki67d after NET in pts with eBC. These characteristics are important to inform clinical trial design and pts selection in clinical practice.

Patients progressed to erdafitinib (n = 14), futibatinib (n = 4) or pemigatinib (n = 3)...In patient-derived models, erdafitinib combined with pictilisib was synergic in the presence of PIK3CA E545K, while erdafitinib-gefitinib combination overcame bypass resistance mediated by EGFR activation.Conclusions We detected a high frequency of FGFR kinase domain mutations at progression to selective FGFR inhibitors in urothelial cancer. Unlike FGFR2-driven cholangiocarcinoma, polyclonality of FGFR3 kinase domain mutations does not seem to be a hallmark of FGFR-driven urothelial cancer. The identification of off-target events and the preclinical validation sustain the potential clinical applicability of combinatorial treatment strategies.

The IC50 values for rapamycin were higher in the low-risk group, whereas those for axitinib, AZD6244, erlotinib, GDC0941, GSK650394, GSK269962A, lapatinib, and PD0325901 were higher in the high-risk group. Therefore, the ubiquitination-related signature is considered a promising tool for predicting a BC patient's immunotherapy response.

EREG is the core onco-immunological biomarker of CuAS and modulates the cross-talk between VEGF and CD99 signaling in glioblastoma, and CuAS may provide support for immunotherapy and chemotherapy.

Among them, seven compounds displayed better activity than lead compound GDC-0941...Moreover, the results of toxicity and hemolysis experiments demonstrated that the most promising compound had low toxicity and good safety. The results of PCR assay and molecular docking modes showed that it was a potential PI3K/mTOR inhibitor, which was worthy of further study.

Of note, PI3K inhibition reveals the strongest anti-migratory effect in Daoy cells. Thus, our in vitro observations provide new insights into different strategies of blocking Rac1 and inhibiting migration in medulloblastoma employing clinically available agents paving the way for confirmatory studies in in vivo models.

We therefore incubated six T-ALL cell lines with four inhibitors of the PI3K/mTOR/AKT pathway (AZD5363, GDC0941, BEZ235 and rapamycin) for 48 and 72hrs and showed surface CD21 up-regulation by flow cytometry of > two-fold at both time points for all inhibitors, with BEZ235 showing the greatest fold increases across all cell lines...When clinically approved PI3K inhibitors (Idelalisib, Duvelisib, Copanlisib, Everolimus) were used, an increase in CD21 expression was again seen across 5 T-ALL cell lines tested...In vivo models analyzing the impact of copanlisib tumor priming on CAR-T efficacy and persistence are ongoing. Target antigen modulation is a promising strategy for enhancing CAR efficacy and reducing risk of antigen negative relapse in low antigen density targets.

The inhibitory activities of XS-2 on ten cancer cell lines were ranging from 1.07 ± 0.11 to 0.002 ± 0.001 μM, which were 1565 times better than that of the lead compound GDC-0941, inhibitory activities against PI3Kα and mTOR kinases were 291.0 and 60.8 nM, respectively...The results showed that XS-2 was expected to be successfully developed as a high-efficiency and low-toxicity breast cancer therapeutic drug with the potential to inhibit the invasion and migration of TNBC. This provides a new research idea for the treatment of TNBC, which is of great significance.

Expression data from DepMap and drug-sensitivity data from ER+ BC cell lines show a positive trend between high MYBL2 expression and sensitivity to the ER degrader, giredestrant. PIC exhibited greater antiproliferative effects in combination with ANA in ER+/HER2- early BC compared to ANA alone, particularly in LumB and MYBL2-high tumors. Furthermore, the transcriptional profile and in vitro response of tumor cells with high MYBL2 expression suggest potential sensitivity to other combination therapies.

ER-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells were exposed to 17β-estradiol (E2, 10 M), Fen (10 M and 10 M), ICI 182,780 (ICI; an ER antagonist, 10 M) or/and Pictilisib (Pic; a PI3K inhibitor, 10 M), and subsequently subjected to migration assay, live cell motility monitoring, trans-chamber assay, immunofluorescence, angiogenesis assay, tumor spheroid formation, and Western blot analysis...Western blot further confirmed the increased expressions of vascular endothelial growth factor (VEGF) and sex-determining region Y-box 2 (SOX2) after exposure to Fen. We conclude that Fen plays an important role as an endocrine-disrupting chemical in breast cancer migration and metastasis through the regulation of ER and PI3K signaling pathways.

To determine how the alterations in N-glycosylation impact glycoprotein dynamics, modeling of changes in glycan interactions of the ITGA5-ITGB1 (Integrin alpha 5-Integrin beta-1) complex revealed specific glycosites at the interface of these proteins that, when highly fucosylated and sialylated, such as in untreated A549 cells, form greater hydrogen bonding interactions compared to the high mannose-types in pictilisib-treated A549 cells. This study highlights the use of mass spectrometry to identify a potential glycosylation inhibitor and assessment of its impact on cell surface glycoprotein abundance and protein-protein interaction.

Using LC-MS/MS-based phosphoproteomics, we found that eukaryotic elongation factor 2 kinase (eEF2K), a key convergence point downstream of MAPK and PI3K pathways, mediates synergism to cotreatment with trametinib plus pictilisib (which target MEK1/2 and PI3Kα/δ, respectively). Systematic analysis in 12 acute myeloid leukemia (AML) cell lines revealed that eEF2K activity was increased in cells for which PI3K plus MEKi co-treatment is synergistic, while PKC potentially mediated resistance to such co-treatment. Together, our study uncovers eEF2K activity as a key mediator of responses to PI3Ki plus MEKi and as a potential biomarker to predict synergy to co-treatment in cancer cells.

Conclusion Targeting PI3-K has pleotropic effects, that include the potential to influence response to a hypoxic microenvironment, both in primary tumours and metastatic sites, such as the bone marrow where it could counteract the osteoclast over-differentiation and activation observed in osteolytic lesions. PI3-K pathway inhibition by GDC-0941 is an effective tool to elucidate the interaction between tumour cells and the bone microenvironment as well as driving mechanisms of breast-to-bone metastases.

Aims To characterize functional responses to 10 PI3Ki in CLL To study PI3Ki drug class activity in idelalisib-refractory CLL To investigate whether ex vivo drug sensitivity can predict in vivo treatment responses Methods CLL cells from patients that were treatment naïve (n=7), idelalisib refractory (n=9), or on idelalisib treatment (longitudinal samples from n=6 patients) were screened against 10 PI3Ki (buparlisib, compound 7n, copanlisib, duvelisib, idelalisib, nemiralisib, pictilisib, pilaralisib, umbralisib, ZSTK474), both alone and in combination with the B-cell lymphoma 2 (Bcl-2) antagonist venetoclax...Ex vivo drug testing on CLL cells from a patient who presented with relapsed disease after sequential treatment with FCR, ibrutinib, idelalisib and venetoclax revealed sensitivity to PI3Ki+venetoclax treatment...Conclusion Our findings indicate PI3Ki drug class activity in idelalisib-refractory CLL, and suggest that ex vivo drug sensitivity may guide precision medicine and predict treatment responses. These results warrant further testing in larger cohorts and in clinical trials.

GDC-0941 promoted ILK expression by upregulating TNF-α level. Taken together, GDC-0941 increased ILK level by upregulating TNF-α, thus affecting AKT expression and the sensitivity of breast cancer cells to GDC-0941.

FGFR1 is an actionable driver oncogene in NB and a promising therapy may consist in targeting FGFR1 mutations in patients with therapy-resistant NB.

Mechanistic characterization of selective responses to the PI3K inhibitor pictilisib, the fatty acid synthase inhibitor GSK2194069, and the SLC16A1 inhibitor AZD3965, bring forth biomarkers of drug response. Phenotypic screening using CLIMET represents a valuable tool to probe cellular metabolism and identify metabolic dependencies at large.

MEK inhibitor showed synergy with multikinase inhibitor ponatinib, ABL inhibitor nilotinib, PI3K/mTOR inhibitor pictilisib, and pan-RAF inhibitor LY3009120. Our preliminary study results suggest that this approach has the potential for larger-scale drug testing and personalized treatment applications in our expansion trial. Our results show that drug sensitivity and resistance testing may be implementable in the treatment planning of patients with MM.

A small-scale screen of inhibitors of bromodomain-containing protein 4 (BRD4; OTX-015), extracellular signal-related kinase (ERK; ulixertinib), mechanistic target of rapamycin (mTOR; AZD-8055), or phosphoinositide 3-kinase (PI3K; GDC-0941) combined with a clinically relevant administration of romidepsin was performed on a panel of uveal melanoma cell lines (92.1, Mel202, MP38, and MP41) and apoptosis was quantified by flow cytometry after 48 hours. Increases in pro-apoptotic BCL2L11 and decreases in anti-apoptotic BIRC5 and BCL2L1 transcripts noted in the sequencing analysis were confirmed at the protein level in Mel202 cells. Our data suggest that romidepsin in combination with mTOR inhibition could be an effective treatment strategy against uveal melanoma due in part to changes in apoptotic proteins.

Patient derived xenograft (PDX) data confirmed that the combination is more effective in abrogating tumor growth with prolonged survival than single-agent treatment (P<0.01). The novel combination of clofarabine and pictilisib in GC promotes DNA damage and inhibits key cell survival pathways to induce cell death beyond single-agent treatment.

This led to the development of sotorasib as a second-line treatment of KRAS mutant non-small cell lung cancer. Considerable effort also has been expended to develop MAP kinase and PI3-kinase pathway inhibitors as indirect RAS antagonists.

An array of newly synthesized thieno[3,2-d]pyrimidine-based derivatives and thienotriazolopyrimidines hybridized with some pharmacophoric anticancer fragments were designed, synthesized and assessed for their in vitro antiproliferative activity against MCF-7 and MDA-MB-231 breast cancer cell lines using erlotinib and pictilisib as reference standards in the MTT assay...Further mechanistic evidences for their anticancer activities were provided by screening the most potent compounds against MCF-7 and/or MDA-MB-231 cells for EGFR and ARO inhibitory activities using erlotinib and letrozole as reference standards respectively...Docking experiments on EGFR and ARO enzymes supported their in vitro results. Thus, the thienotriazolopyrimidines 11b and 12 showing good EGFR inhibition and the thieno&lsqb;3,2-d]-pyrimidine derivatives 3b and 9d, eliciting the best ARO inhibition activity, can be considered as new candidates as anti-breast cancer agents that necessitate further development.

Prevention of estrogen receptor-negative (ER-) breast cancer is an unmet challenge, although tamoxifen and aromatase inhibitors can successfully decrease the incidence of ER-positive (ER+) breast cancer...Both genetic knockdown of PIK3CA or intervention with low-doses of a PI3K inhibitor (GDC-0941) prevented the dysplasia phenotype of semi-transformed human ER- mammary epithelial cells in 3-dimensional culture in vitro...In human ER- breast cancer, PI3K activation is correlated with significantly reduced CCL5, CXCL10 and CD8A expression, suggesting that the decreased CD8 T-cell recruitment and escape of immune surveillance may contribute to ER- breast cancer development. In summary, our study indicates that low-dose PI3K inhibitor treatment may intervene early stage ER- breast cancer development by enhancing immune surveillance via CCL5/CXCL10.