BMS-754807

Finally, according to our model and computational drug sensitivity analysis, four small molecule compounds, BMS-754807, SB216763, Doramapimod, and Trametinib, were identified as potential therapeutic agents for patients with MCL. This study provides a prognostic model with ferroptosis-related gene signature for MCL. The results show that the model helps predict prognosis in MCL.

Our results suggest that the LD-M risk score is an effective prognostic indicator for individualized treatment of LUAD.

BMS-754807 with nab-paclitaxel produced substantially greater antitumor effects by increasing in vivo apoptosis, leading to increased mice survival compared to those of BMS-754807 or nab-paclitaxel monotherapy. Our outcomes support the use of BMS-754807, alone and in combination with nab-paclitaxel, as an efficient and innovative treatment choice for EAC.

Despite resistance to immunotherapy, the high-risk group showed sensitivity to molecular targeted agents directed at IGF-1R (BMS-754807) and the PI3K-mTOR pathways (AZD8186, AZD8055). This study unveils the intricate interplay between TME and metabolic pathways in gastric cancer, offering potential for enhanced diagnosis, patient stratification, and personalized treatment. Understanding molecular features in each subtype enriches our comprehension of gastric cancer heterogeneity and potential therapeutic targets.

Thus, we tested whether inhibition of insulin receptor/insulin-like growth factor 1 receptor with the drug BMS-754807 and/or lysosomal disruption with hydroxychloroquine (HCQ) could sensitize TNBC cells to the chemotherapy drug carboplatin. Additionally, we demonstrate the lack of overt in vivo toxicity with our combination regimens and, therefore, propose that metabolic targeting of TNBC may be a safe and effective strategy to increase sensitivity to chemotherapy. Thus, we conclude that the use of exogenous metabolic modulators, such as BMS-754807 or HCQ, in combination with chemotherapy warrants additional study as a strategy to improve therapeutic responses in women with TNBC.

IL4I1 may play a role as promoter of cancer and prognostic indicator in patients. High expression of IL4I1 is associated with the state of tumor immunosuppression and may contribute to tumor-associated macrophage invasion. Therefore, IL4I1 may be a new therapeutic target for the treatment and prognosis of patients with cancer.

Our findings emphasizes the role of disulfidptosis in regulating tumor development, therapeutic response, and patient survival in CRC patients. For the clinical treatment of CRC, these important LncRNAs could serve as viable therapeutic targets.

In addition, drug sensitivity analysis identified 3 compounds, including BMS-754807, cytochalasin b, and linifanib, that could have a potential therapeutic effect on patients with the BLIS subtype. The risk prognosis model showed good prognostic value for the BLIS subtype patients, and the ten lncRNAs may be potential therapeutic targets.

Moreover, we demonstrated an inverse correlation between GPD1L expression and therapeutic response for three therapeutic agents (PF-562271, Linsitinib, and BMS-754807), highlighting its potential as a predictive biomarker for HCC treatment outcomes. These data provide insights into the prognostic significance, molecular characteristics, and predictive potential of GPD1L in HCC.

These effects were reversed by the pharmacological inhibition of IGFR with BMS754807...Our findings suggest that CR in association with reduced IGF1 levels could upregulate miR-15b to downregulate Igf1r and contribute to the anticancer effects of CR. Thus, miR-15b may be a therapeutic target for mimicking the beneficial effects of CR against TNBC.

This study established a promising HRCA-PDO biobank and conducted the first high-throughput and high-content HRCA drug screening in order to shed light on the prevention of colorectal cancer.

Based on these gene signatures, we investigated 3 small compounds, namely cucurbitacin I, BMS-754807, and PHA-793887 as potential candidates for the treatment of cancer. Future studies on the mechanisms associated with the revealed gene signatures and anticancer effects of these three small compunds would allow scientists to develop therapeutic approaches to combat cancer. This research contributes to the evaluation of mechanisms and gene signatures that either limit or cause cancer, and to the development of new cancer therapies by establishing a link between regeneration and carcinogenesis.

Four drugs including metformin, BMS754807, Panobinostat, and AT9283 were screened out as potential hits with generally consistent inhibitory efficacy on HRCA-PDOs. This study established a promising HRCA-PDO biobank and conducted the first high-throughput and high-content HRCA drug screening in order to shed light on prevention of colorectal cancer.

Furthermore, dasatinib (18 mg/kg) in combination with BMS-754807 (18 mg/kg) inhibited the growth of tumors in NCI-H3255 xenografts without changing the bodyweight. Overall, our results suggest that dasatinib in combination with BMS-754807 inhibits the lung cancer cell proliferation in vitro and tumor growth in vitro, which indicates promising evidence for the application of the drug combination in lung cancer therapy.

Furthermore, our model provided personalized survival probability predictions with a concordance index of 0.795 and identified the drug candidate BMS-754807 as a potentially sensitive treatment option for lung adenocarcinoma. In summary, we presented a deep neural network prognostic model for lung adenocarcinoma, based on nine cuproptosis-related genes, which offers independent prognostic capabilities. This model can be used for personalized predictions of patient survival and the identification of potential therapeutic agents for lung adenocarcinoma, which may ultimately improve patient outcomes.

In conclusion, our data underline an essential role of CREB in SySa tumorigenesis and provides evidence for molecular targeted therapies.

In line with this, 10 Gy SD cells were more sensitive to target inhibition with Capivasertib or Ipatasertib (AKTi), BMS-754807 (IGF-1Ri), or Foretinib (VEGFR2/METi), but less sensitive to Panobinostat or Vorinostat (HDACi). In summary, understanding the molecular short- and long-term changes after irradiation can aid in optimizing the efficacy of multimodal radiation oncology in combination with post-irradiation molecularly-targeted drug treatment and improving the outcome of prostate cancer patients.

Using prostate cancer cell lines DU145 and 22Rv1 we detected nuclear α- and β-subunits, with increase in nuclear signal upon IGF-treatment and reduction in response to IGF-1R inhibitor BMS-754807...Finally, we detected recruitment of both subunits to regulatory regions of chromatin, including the promoter of the oncogene JUN, that we previously identified in ChIP-seq as sites of IGF-1Rβ enrichment. These data confirm the cell surface origin of nuclear IGF-1R, suggest the presence of nuclear αβ complexes and reveal that both IGF-1Rα- and β-subunits contribute to pro-tumorigenic functions of nuclear IGF-1R.

The combination of dabrafenib, trametinib, and BMS-754807 treatment reduced in vivo xenograft tumor growth. Examining the role of IGF1R and IR in mediating resistance to BRAF and MEK inhibitors will expand possible treatment options to aid in long-term success for BRAF-mutant melanoma patients.

In addition, we observed that flavopiridol alone or in combination with the chemotherapeutic agent nanoparticle albumin-bound paclitaxel (NPT) or in combinations with the targeted agent BMS-754807 significantly inhibited esophageal cancer cell proliferation and subcutaneous xenograft tumor growth while significantly enhancing overall mice survival. These results indicate that aggressive esophageal cancer cells with elevated c-Myc expression are sensitive to the CDK inhibitor flavopiridol, and that flavopiridol alone or in combination can be a potential therapy for c-Myc overexpressing esophageal cancer.

Focal Adhesion Kinase (FAK) and Paxillin phosphorylation were decreased as early as 15 min after treatment, and treatment with a FAK inhibitor, PF-562,271, was sufficient to decrease viability in vitro. Most strikingly, treatment with BMS754807 and dasatinib, or a FAK inhibitor alone, significantly increased cleaved-PARP in human ex-vivo HNSCC patient tissues demonstrating a potential clinical utility for targeting FAK or the combined targeting of the IGF1R with Src. This ex-vivo result further confirms FAK as a vital signaling node of this combinatorial treatment and demonstrates therapeutic potential for targeting FAK in HNSCC patients.

Using prostate cancer cell lines DU145 and 22Rv1 we detected nuclear α- and β-subunits, with increase in nuclear signal upon IGF-treatment and reduction in response to IGF-1R inhibitor BMS-754807...These data confirm the cell surface origin of nuclear IGF-1R, suggest the presence of nuclear αβ complexes and reveal that both IGF-1Rα- and β-subunits contribute to pro-tumorigenic functions of nuclear IGF-1R. The online version contains supplementary material available at 10.1007/s12672-021-00407-8.

This data suggest that IGF2 is a potential biological marker for breast cancer disparities and that targeting receptors of IGF2 with drugs such as BMS-754807 could provide additional treatment options in combination with current therapies, thus reducing TNBC progression and ultimately improving patient outcomes. [Funded by NIH U54 143931 Cancer Center Partnership and CBCRP]

To mimic CR in vitro, and to test the effects of miRNA manipulation, the C3-Tag series of TNBC cell lines were treated (separately and in combination) with serum restriction, BMS754807 (inhibitor of IGF1-R), and various levels of recombinant IGF-1 as well as manipulated levels of miRNA’s associated with IGF-1/mTOR signaling...Together these findings suggest that reduced circulating IGF-1 levels in response to CR leads to the upregulation of miR-15b, which correspondingly targets and downregulates IGF-1R, both at the mRNA and protein levels. This combination of reduced IGF-1 ligand and miR-15b-induced IGF-1R downregulation contributes to the potent anticancer effects of CR and reveals potential targets for pharmacologically mimicking those effects.

Two radio-resistant colorectal cancer cell lines, SW480 and HT29, were selected for in vitro studies, and the involvement of the IGF1R in their radiation resistance was elucidated by suppressing its expression through a targeted siRNA and through the use of a specific IGF1R inhibitor, BMS-754807...This study supports the notion that the radiosensitivity of radiation-resistant colorectal cancer cells can be enhanced by directly targeting IGF1R expression or activity. Ultimately, the combination of radiotherapy with IGF1R targeted inhibitors could potentially increase its effectiveness in the treatment of advanced colorectal cancer.

Taken together, our results are indicative that BMS mainly acts through off-target effects exerted on other protein kinases. Given that BMS exhibits a potent antiproliferative effect, we believe that this compound could be useful for the treatment of different types of tumors independently of their IGF-1R activation status.

In addition, we experimentally validated predicted synergy of the BRAF/insulin receptor combination (Dabrafenib/BMS-754807) in 48 colorectal cancer cell lines. We anticipate that our approaches can be used for prioritization of drug combinations in large scale screenings, and to maximize the efficacy of drugs already known to induce synergy, ultimately enabling patient stratification.

We conclude that the combination of metformin and BMS-754807 is more effective than either drug alone in inhibiting cell proliferation in the majority of TNBC cell lines, and that one important mechanism may be suppression of SCF and subsequent stabilization of the cell cycle inhibitor p27. This combination treatment may represent an effective targeted therapy for a significant subset of TNBC cases and should be further evaluated.

Here, we discovered that prolonged treatment of colon cancer cells with IGF-1R inhibitors (BMS-754807 and GSK1838705A) stimulates p70 KDa ribosomal protein S6 kinase 1 (p70S6K1) activation, a well-known kinase signaling for cell survival. Furthermore, the combination of BMS-754807 and U0126 efficiently decreased the cell viability and increased cleaved caspase 3 and apoptosis in vitro and in vivo. Our data suggest that the treatment of colon tumor cells with IGF-1R inhibitors stimulates p70S6K1 activity via MEK1/2 to promote survival, providing a new strategy for colorectal cancer therapeutics.

Fixed-ratio combination cytotoxicity assays using the tyrosine kinase inhibitors BMS-754807 and ponatinib that target IGF1R and FGFR1, respectively, revealed strong synergy against both cell line and patient-derived xenograft (PDX) models of CRLF2r Ph-like ALL. While this study identified potential new targets in CRLF2r Ph-like ALL, it also highlights that in vivo validation of synergistic drug interactions is essential. Implications: Quantitative phosphotyrosine profiling identified potential therapeutic targets for high-risk CRLF2-rearranged Ph-like ALL.

Combination treatment of BMS-754807 (IGF1R/IR) with NVP-AEW541 (IGF1R inhibitor) reduced proliferation of human MDA-MB-231, BT549, HCC1937 and murine 4T1 TNBC cells in vitro (P<0.001). Use of immunotherapy is a promising management option for a subset of TNBC patients, and combination treatments using IGF1R antagonists with immune checkpoint inhibitor may constitute a new treatment strategy to combat this deadly disease. &lsqb;Funding by NCI U54 CA1433930; California Breast Cancer Research Program; UCLA Jonsson

We showed that both MAPK and IGF1R pathway inhibition, using the ERK inhibitor SCH772984 and the IGF1R inhibitor BMS-754807, respectively, restored BRAFi sensitivity in melanoma cells lacking HAT1. Collectively, we show that the loss of HAT1 expression confers acquired BRAFi resistance by activating the MAPK signaling pathway via IGF1R.