saracatinib (AZD0530)

Collectively, this study enhanced our understanding of NENA NSLA by elucidating the proteogenomic landscape and proposed saracatinib as a potential treatment for this patient population that lacks effective targeted therapies. The proteogenomic landscape in never-smoker lung cancer without known driver mutations reveals prognostic proteins and enhanced estrogen signaling that can be targeted as a potential therapeutic strategy to improve patient outcomes.

P1/2, N=49, Recruiting, National Jewish Health | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Dec 2023 --> Sep 2024

In an imiquimod (IMQ)-induced psoriasis mouse model, saracatinib effectively blocked MLKL phosphorylation and inflammatory responses in vivo. Taken together, these findings indicate that saracatinib inhibits necroptosis by targeting MLKL, providing a potential therapeutic approach for skin inflammation-related diseases such as psoriasis.

Besides, compared to the low-risk group, there were higher expressions of most immune checkpoint genes and HLA genes in the high-risk group, and the high-risk patients showed higher sensitivity to the chemotherapy and targeted drugs (axitinib, dasatinib, pazopanib, saracatinib, sunitinib and temsirolimus). The novel CRG signature may act as a reliable, efficient tool for prognostic prediction and treatment guidance in future clinical practice.

This study provides a characterization of the signaling pathways and effector genes involved in CAFs activation, and strategies that could effectively inhibit it in the context of GC. Video Abstract.

Based on the m6A/m5C/m1A-related genes in LUAD, LUAD patients were divided into 2 subtypes, and a m6A/m5C/m1A-related LUAD prognostic model was constructed to provide a reference for the prognosis prediction of LUAD.

BMP signalling pathway is important for CML cell survival. Targeting SRC, ABL and ALK kinases is more effective than ABL inhibition alone, the combination efficacy importantly being demonstrated in both 2D and 3D cell cultures highlighting the need for combinatorial therapies in contrast to standard of care single agents. Our study provides justification to target multiple kinases in CML to combat LSC persistence.

It can also optimize the administration of various first-line drugs, including AKT inhibitors VIII Imatinib, Crizotinib, Saracatinib, Erlotinib, Dasatinib, Rapamycin, Roscovitine and Shikonin in BC patients. Finally, we employed machine learning techniques to construct a multi-omics prediction model(Risklight),with an area under the feature curve (AUC) of up to 0.89. With the help of CAG_score and Risklight, we reveal the signature of cholesterol homeostasis-related genes for angiogenesis, immune responses, and the therapeutic response in breast cancer, which contributes to precision medicine and improved prognosis of BC.

This study introduced an innovative multiomics data analysis pipeline. Using this approach, we successfully identified 4 molecular subtypes of lung adenocarcinoma as well as their candidate therapeutic agents. The newly identified subtypes can be combined with the current biomarkers to generate a comprehensive roadmap for treatment decision-making.

Despite study heterogeneity, this review shows that ICI could be a therapeutic option for selected patients with TET that are not amenable to curative radical treatment after first-line chemotherapy.

To target this mechanism, we showed that an inhibitor of SRC, saracatinib, blunts the VAV1-induced transcriptional reprogramming. Overall, we highlighted the importance of accounting for melanoma heterogeneity in treating cutaneous melanoma with MAPK inhibitors. Moreover, we demonstrated the utility of the Sleeping Beauty transposon system in understanding cancer drug resistance.

Drugs like trametinib, saracatinib, and dasatinib may be used in patients with high POLD4. Using experimental analysis, we further confirmed the overexpression of POLD4 in gliomas, as well as its correlation with glioma recurrence, proliferation, and the suppressive immune microenvironment. Our research findings indicate that the expression pattern of POLD4 not only serves as a robust indicator of prognosis in cancer patients but also holds promising potential as a new focus for treatment.

ErbB inhibitors (canertinib and sapitinib) or erbB3 knockdown in combination with Src (saracatinib), calmodulin [trifluoperazine (TFP)], or proviral integration site of Moloney murine leukemia kinase (AZD1208) inhibition even more effectively reduces proliferation and survival. Src inhibition (saracatinib), like erbB3 knockdown, prevents these phosphorylation events and when combined with trifluoperazine even more effectively reduces proliferation and survival compared to monotherapy. Our findings implicate erbB3, calmodulin, PIM kinases and Src family members as important therapeutic targets in MPNSTs and demonstrate that combinatorial therapies targeting critical MPNST signaling pathways are more effective.

A novel scoring system based on macrophage subclusters was constructed, thereby guiding more effective prognostic evaluation and tailored potential drug agents strategies of HCC patients.

The stemness-based subtypes shed novel insights into the potential roles of LUSC-stemness in tumor heterogeneity, and our prognostic signatures offer a promising tool for prognosis prediction and guide therapeutic decisions in LUSC.

Second generation hormonal therapies such as abiraterone acetate and enzalutamide are typically given to men with CRPC. Lastly, we also found that the saracatinib-enzalutamide combination reduced DNA replication compared to the saracatinib-docetaxel combination, resulting in marked increased apoptosis. By elucidating this combination strategy, we provide pre-clinical data that suggests combining SRC kinase inhibitors with enzalutamide in select patients that express both AR-FL and AR-Vs.

Inhibition of BCR-ABL (Imatinib), Flt3 (Quizartinib) or Src-Kinase-Family (Saracatinib) leads to significant reconstitution of SHIP1 protein expression. These results further support a functional role of SHIP1 as tumor suppressor protein and could be the basis for the establishment of a targeted therapy form.

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.

All cell lines were treated with Src inhibitors, saracatinib (SAR) and dasatinib (DAS), with concentration ranging from 0.02 to 10.00 µM. Src tyrosine kinase inhibitors combined with SOR therapy may provide a potential treatment advantage in HCC to comprise cellular heterogeneity.

CCL2 expression is regulated through the EGFR/Src-dependent signaling in HER2+ breast cancer.

After being treated with saracatinib, we observed significantly decreased protein levels of p-ERK, matrix metallopeptidase 2 (MMP-2), MMP-3, MMP-9, Cyclin D1, and Cyclin A2 in the SW480 cells. In conclusion, PLAU affects the migration, invasion, and proliferation of CRC cells by activating the Src/ERK pathway.

These findings contribute to understanding of the function of m6A-related lncRNAs in UCEC and provide promising therapeutic strategies for UCEC.

This study revealed the effects of CRLs on BCa and further established CRLs model, which can be used in clinic for predicting prognosis, immunological response and treatment sensitivity inpatient with BCa.

Crucially, SFKs promoted YAP nuclear localization and phosphorylation at Tyr357, as shown by using the SFK inhibitors dasatinib, saracatinib, the preferential YES1 inhibitor CH6953755, siRNA-mediated knockdown of YES1, and transfection of epitogue-tagged YAP mutants in PANC-1 and Mia PaCa-2 cancer cells, models of the aggressive squamous subtype of PDAC. A combination of dasatinib and trametinib potently and synergistically inhibited colony formation by PDAC cells and suppessed the growth of MiaPaCa-2 cells xenografted into the flank of nude mice. The results provide rationale for considering a combination(s) of FDA-approved SFK (dasatinib) and MEK (e.g. trametinib) inhibitors in prospective clinical trials for the treatment of PDAC.

By elucidating this synergy, we will provide critical pre-clinical data that could influence how future clinical trials are designed to increase the survival for men suffering from lethal CRPC. Learning Objective 1: Combination Therapy with kinase inhibitors may be a possible avenue to pursue in treating prostate cancer Learning Objective 2: Enzalutamide plus Saracatinib synergize together to yield greater prostate cancer cell death.

Clinical trials in rare diseases with limited study populations pose unique challenges. An ideal solution for limiting risks in early clinical studies is drug repositioning - using existing clinical molecules for new disease indications. Using existing assets may also allow a more fluid transition into clinical practice. With positive study outcome, AZD0530 may provide a therapy for FOP that can be rapidly progressed due to the availability of existing safety data from 28 registered clinical trials with AZD0530 involving over 600 patients.

Our in vivo and in vitro data demonstrated that SRC inhibitor saracatinib enhance T-cell-mediated anti-tumor immune responses in non-small lung cancer. We also provide evidence that support the combination of saracatinib and anti-PD-1/PD-L1 as a potential combination therapeutic approach to increase the efficacy of immunotherapy in non-small lung cancer.

The three-drug combination of inhibitors of CRM1 (Selinexor), AKT (MK-2206), and SRC (Saracatinib), which is well-tolerated in mice, induced potent inhibition of tumor xenograft growth and was associated with induction of markers of apoptosis and senescence. Interestingly, KRAS siRNA knockdown phenocopied CRM1 inhibition, as it reduced cytoplasmic EZH2, DLC1 methylation, and DLC1 degradation. Our findings suggest CRM1 inhibitors, when given in conjunction with AKT and/or SRC kinase inhibitors, may have clinical efficacy against lung tumors with mutant KRAS.

A post-hoc validation of the assay was possible by comparing the activity of a drug in our assay with early evidence of activity in human OS clinical trials (regorafenib and saracatinib). Despite the biological rationale, we found no evidence to support the use of oclacitinib as an antimetastatic agent in OS. The findings support our 3D BME assay as a highly efficient method to examine drugs for activity in targeting OS DTCs.

Material and Methods We used four SFK inhibitors: dasatinib, bosutinib, saracatinib, and bafetinib, and measured sensitivity to these drugs for 30 cancer cell lines belonging to 12 different cancer types...Doxorubicin increased expression of all SFKs in HT-29 colon cancer cells and, in combination with dasatinib, also had a synergistic effect on cell growth...These findings have the potential to improve future strategies for the use of SFKs inhibitors in cancer treatment. This study was funded by RFBR, project number 20-34-70119.

Material and Methods We used four SFK inhibitors: dasatinib, bosutinib, saracatinib, and bafetinib, and measured sensitivity to these drugs for 30 cancer cell lines belonging to 12 different cancer types...Doxorubicin increased expression of all SFKs in HT-29 colon cancer cells and, in combination with dasatinib, also had a synergistic effect on cell growth...These findings have the potential to improve future strategies for the use of SFKs inhibitors in cancer treatment. This study was funded by RFBR, project number 20-34-70119.

Material and Methods We used four SFK inhibitors: dasatinib, bosutinib, saracatinib, and bafetinib, and measured sensitivity to these drugs for 30 cancer cell lines belonging to 12 different cancer types...Doxorubicin increased expression of all SFKs in HT-29 colon cancer cells and, in combination with dasatinib, also had a synergistic effect on cell growth...These findings have the potential to improve future strategies for the use of SFKs inhibitors in cancer treatment. This study was funded by RFBR, project number 20-34-70119.

Material and Methods We used four SFK inhibitors: dasatinib, bosutinib, saracatinib, and bafetinib, and measured sensitivity to these drugs for 30 cancer cell lines belonging to 12 different cancer types...Doxorubicin increased expression of all SFKs in HT-29 colon cancer cells and, in combination with dasatinib, also had a synergistic effect on cell growth...These findings have the potential to improve future strategies for the use of SFKs inhibitors in cancer treatment. This study was funded by RFBR, project number 20-34-70119.

C1 was more sensitive to eight chemotherapy drugs (A.443654, AZD.0530, AZD6482, AZD7762, AZD8055, BAY.61.3606, Bicalutamide, and CGP.60474). Our study characterized two ferroptosis-related subtypes with distinct prognosis and tumor immune features, which could assist clinicians make decisions and individual therapy. Moreover, 15 ferroptosis-related mRNAs were identified, which could become potential therapeutic targets for ovarian cancer.

In H1975 lung cancer cells with activated Src, blocking Rpt2-Y439 phosphorylation by the Y439F mutation conferred partial resistance to the Src inhibitor saracatinib both in vitro and in a mouse xenograft tumor model, and caused significant changes of cellular responses to saracatinib at the proteome level. Our study has defined a novel mechanism involved in the spatial regulation of proteasome function and provided new insights into tyrosine kinase inhibitor-based anticancer therapies.

This work suggests that SRC activation may be a potential mechanism of PARPi resistance and that treatment with SRC inhibitors may overcome this resistance. Our preclinical study demonstrates that combining PARPi and SRC inhibitors may be a promising therapeutic strategy for patients with BRCA2-null mCRPC.

Furthermore, Saracatinib (Src inhibition) and BI2536 (PLK1 inhibition) diminished GSC self-renewal in vitro, and combining the two inhibitors increased survival of orthotopic tumor-bearing mice. Taken together, these data indicate that p-Src and PLK1 contribute to cancer stemness in EGFRvIII-positive GSCs by driving Notch1-SOX2 signaling, a finding that has important clinical implications.

The IGF2BP1-SRC/ERK2 axis is targetable by the SRC-inhibitor saracatinib and MEK-inhibitor selumetinib. In conclusion, we reveal an unexpected role of IGF2BP1 in enhancing SRC/MAPK-driven invasive growth of ovarian cancer cells. This provides a rationale for the therapeutic benefit of combinatorial SRC/MEK inhibition in mesenchymal-like HGSOC.