dactolisib (RTB101)

Reversible resistance to NVP-BEZ235 in ccRCC is driven, at least in part, by an m6A-dependent YTHDF3-SYNM axis. Targeting YTHDF3 or SYNM may provide a rational strategy to overcome PI3K/mTOR inhibitor resistance in ccRCC.

In a MECOM-r AML PDX model, mivebresib with dactolisib or LCL161, was superior to monotherapy or vehicle in reducing AML burden and increasing mouse survival. These findings highlight that cotreatment with BETi and PI3K/mTOR or IAP inhibitor exerts superior in vitro and in vivo efficacy in MECOM-r AML cells and support further evaluation of these BETi-based combinations.

Co-inhibition of mTOR or the SLC3A2/SLC7A5 complex using dactolisib or JPH203 restores sensitivity to KRAS inhibitors in vitro and in vivo. These findings support combinatorial targeting of mTOR signaling or amino acid transport to overcome intrinsic resistance in KRAS-mutant lung cancer.

Mechanistically, FFAs were found to trigger Akt activation, and pharmacological inhibition of this protein by BEZ235 could successfully counteract their cancer-promoting effects. Collectively, these results support the presence of an EV-driven bidirectional interplay between PCa cells and adipocytes, which reprograms the latter toward a lipolytic, tumor-promoting phenotype.

Triple-Negative Breast Cancer can develop resistance to gemcitabine and overcoming this resistance is critical for effective treatment. In silico analysis using GEPIA revealed a relation between hENT1 with Mcl-1 and Bcl2. These findings reveal ABT-737 and NVP-BEZ235 attenuate MDA-MB-231GEMR cell line and show potential implication on reversing resistance in TNBC for further studies.

Through drug sensitivity analysis, several drugs exhibited significant correlation with risk score, and molecular docking illustrated that both dactolisib and linsitinib were capable of binding tightly with most signature genes, making them potential candidates for targeted therapeutic approaches of LGG. Thus, this model can stratify LGG patients with distinct gene expression features, immune landscape, genomic instability and microbiota features. By stratifying patients with risk score, this risk model may improve the accuracy of prognostic prediction for LGG patients, which might provide new insights into the molecular targeted therapy for individual treatment in a risk score-specific manner.

mTOR inhibitors such as everolimus and BEZ235 have demonstrated efficacy in pancreatic neuroendocrine tumors (PanNET) at the cost of severe side effects, and no biomarker currently predicts response. High expression of CAIX and LDHA, two markers of pseudohypoxia/glycolysis, was associated with shorter progression-free survival in patients treated with everolimus. This study demonstrates that tissue culture can effectively assess drug response in PanNET and identifies a pseudohypoxic/glycolytic profile as a determinant of resistance to mTOR inhibition, detectable by immunohistochemistry and potentially noninvasively by 18FDG PET-CT.

The study used mTOR kinase inhibitors: Everolimus and Torkinib; dual PI3K/mTOR inhibitors BEZ-235 and Omipalisib; and the mTORC1/2 inhibitor OSI-027. These compounds were used both as monotherapy and in combination with the MEK1/2 inhibitor AS-703026...The morphology of cells also changed significantly: their thickness, volume, roughness, convexity of shape, and irregularity, which may be a good diagnostic and prognostic factor for the response to treatment. Our studies to date on the effect of three generations of mTOR kinase inhibitors on the inhibition of the invasion process, the activation of apoptosis, and the reduction in cell proliferation suggest that they may be an important target for anticancer therapy.

Ligand tracer results show that the combination of Berberine and NVP-BEZ235 reflects the stabilizing effect of NVP-BEZ235 on Berberine binding kinetics in MDA-MB-231 cells. These findings suggest a synergistic effect of NVP-BEZ235 and Berberine combination inhibiting metastasis of MDA-MB-231 cell line, demonstrating a potential therapy for TNBC.

Diabetes plays an important role in CC pathogenesis, and NVP-BEZ235 may be a promising therapeutic drug for CC patients with diabetes.

Collectively, these findings demonstrate that NVP-BEZ235 facilitates tau clearance by enhancing autophagy through mTOR inhibition, thereby mitigating cognitive deficits and neuroinflammation in tauopathy models. This study supports the therapeutic potential of NVP-BEZ235 as a promising candidate for the treatment of tau-related neurodegenerative diseases.

Bcl-2 inhibitor ABT-737 and Mcl-1 inhibitor AZD5991 predisposed NVP-BEZ235-treated cells to transform into the apoptotic phenotype. PI3K inhibitor LY294002 and Stat3 inhibitor AG490 duplicated the sensitized actions towards NVP-BEZ235...Data of in vivo tumor-bearing studies further revealed a better anti-tumor potential in the combination treatment of NVP-BEZ235 and MEK/ERK inhibitors without obvious toxicity. Our findings suggest that the feedback activation of pro-survival machinery is likely to be the main cause of cancer cells being refractory to NVP-BEZ235, and a combination treatment is a feasible strategy to sensitize cancer cell responses.