Combined inhibition of PI3K and Src kinases demonstrates synergistic therapeutic efficacy in clear-cell renal carcinoma

Roelants, Caroline; Giacosa, Sofía; Pillet, Catherine; Bussat, Rémi; Champelovier, Pierre; Bastien, Olivier; Guyon, Laurent; Arnoux, V.; Cochet, Claude; Filhol, Odile

doi:10.18632/oncotarget.25700

Cited by 12 publications

(13 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the potential clinical benefits of these molecules are tempered because tumors ultimately progress regardless of these therapies and few patients are cured of this disease [ 97 ], thus calling for combined intervention on complementary pathways that can engender drug resistance to individual targeted drugs. In this vein, we previously showed that combined inhibition of phosphatidylinositol 3-kinase (PI3K) and Src kinases exhibits synergistic therapeutic efficacy in clear-cell renal carcinoma [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

“…All animal studies were approved by the institutional guidelines and those formulated by the European Community for the Use of Experimental Animals. Renal orthotopic implantation was carried out by injection of 3 × 10 6 786-O luc cells into the left kidney of athymic nude mice as previously described [ 50 ]. Two patient derived xenograft (PDX) models, RCC43B and RCC-10-B, were generated by Xentech (Paris France).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction

Giacosa

Pillet

Séraudie

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

Kinase-targeted agents demonstrate antitumor activity in advanced metastatic clear cell renal cell carcinoma (ccRCC), which remains largely incurable. Integration of genomic approaches through small-molecules and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. The 786-O cell line represents a model for most ccRCC that have a loss of functional pVHL (von Hippel-Lindau). A multiplexed assay was used to study the cellular fitness of a panel of engineered ccRCC isogenic 786-O VHL− cell lines in response to a collection of targeted cancer therapeutics including kinase inhibitors, allowing the interrogation of over 2880 drug–gene pairs. Among diverse patterns of drug sensitivities, investigation of the mechanistic effect of one selected drug combination on tumor spheroids and ex vivo renal tumor slice cultures showed that VHL-defective ccRCC cells were more vulnerable to the combined inhibition of the CK2 and ATM kinases than wild-type VHL cells. Importantly, we found that HIF-2α acts as a key mediator that potentiates the response to combined CK2/ATM inhibition by triggering ROS-dependent apoptosis. Importantly, our findings reveal a selective killing of VHL-deficient renal carcinoma cells and provide a rationale for a mechanism-based use of combined CK2/ATM inhibitors for improved patient care in metastatic VHL-ccRCC.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction

Giacosa

Pillet

Séraudie

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…We first compared the induction of cell mortality in 786-O spheroids after their treatment with either a combination of GDC-0941 and saracatinib (GDC/SRC), two small-molecule inhibitors that target the PI3K and Src kinases respectively [39], or the currently clinically used inhibitors sunitinib, pazopanib, or temsirolimus at the indicated concentrations. Treated spheroids were recorded for 48 h using an Essen IncuCyte Zoom live-cell microscopy instrument ( Figure 1A).…”

Section: Evaluation Of Drug Sensitivity On 786-0 Cell-derived Spheroidsmentioning

confidence: 99%

“…In this study, we developed different biological cell-based systems like 3D tumor spheroids, mice orthotopic tumor xenografts, and patient-derived tumor slice cultures (PDTSC) for ex-vivo assessment of drug effects in renal carcinoma. As we recently showed, a combination of two inhibitors targeting both the PI3K and Src kinases impedes cell viability of renal carcinoma cells [39], we compared the efficacy of this combination to standard-of-care-drugs for RCC like sunitinib, pazopanib, and temsirolimus using 3D tumor spheroids and PDTSC methods. We show that PDTSC has the potential to be exploited for cancer cell sensitivity assessment to novel molecularly targeted therapies among patients with ccRCC, and to identify suitable candidates for drug combinations in a cost-effective and patient-friendly manner.…”

Section: Introductionmentioning

confidence: 99%

Ex-Vivo Treatment of Tumor Tissue Slices as a Predictive Preclinical Method to Evaluate Targeted Therapies for Patients with Renal Carcinoma

Roelants

Pillet

Franquet

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

Clear cell renal cell carcinoma (ccRCC) is the third type of urologic cancer. At time of diagnosis, 30% of cases are metastatic with no effect of chemotherapy or radiotherapy. Current targeted therapies lead to a high rate of relapse and resistance after a short-term response. Thus, a major hurdle in the development and use of new treatments for ccRCC is the lack of good pre-clinical models that can accurately predict the efficacy of new drugs and allow the stratification of patients into the correct treatment regime. Here, we describe different 3D cultures models of ccRCC, emphasizing the feasibility and the advantage of ex-vivo treatment of fresh, surgically resected human tumor slice cultures of ccRCC as a robust preclinical model for identifying patient response to specific therapeutics. Moreover, this model based on precision-cut tissue slices enables histopathology measurements as tumor architecture is retained, including the spatial relationship between the tumor and tumor-infiltrating lymphocytes and the stromal components. Our data suggest that acute treatment of tumor tissue slices could represent a benchmark of further exploration as a companion diagnostic tool in ccRCC treatment and a model to develop new therapeutic drugs.

show abstract

“…Besides, c-src tyrosin kinase has been shown to be abnormally activated or over-expressed in a number of different malignancies and to stimulate processes associated with tumour progression, such as proliferation, angiogenesis or metastasis (10). Src tyrosin kinase inhibitors have been explored as potential new therapies in a variety of malignancies such as melanoma (one such inhibitor showing in vitro that is active on a variety of melanoma cells, including some BRAF V600 mutant cells (11), but a report that src inhibition would increase induces melanogenesis in melanoma cells has also been published (12)), papillary thyroid carcinoma (13), clear-cell renal carcinoma (14), pancreatic (15) or ovarian cancer (16). The space of the universe is expanding, but so is the "chemical space".…”

Section: Introductionmentioning

confidence: 99%

Use of QSAR Global Models and Molecular Docking for Developing New Inhibitors of c-Src Tyrosine Kinase

Ancuceanu

Tamba

Stoicescu³

et al. 2019

Preprint

View full text Add to dashboard Cite

Prototype of a family of at least nine members, c-src tyrosine kinase is a therapeutically interesting target, because its inhibition might be of interest not only in a number of malignancies, but also in a diverse array of conditions, from neurodegenerative pathologies to certain viral infections. Computational methods in drug discovery are considerably cheaper than conventional methods and offer opportunities of screening very large numbers of compounds in conditions that would be simply impossible within the wet lab experimental settings. We have explored the use of global QSAR models and molecular ligand docking in the discovery of new c-src tyrosine kinase inhibitors. Using a data set of 1038 compounds from ChEMBL and 19 blocks of molecular descriptors, we have developed over 200 QSAR classification models, based on six machine learning algorithms and 17 feature selection methods. We have selected 49 with reasonably good performance (positive predictive value and balanced accuracy higher than 70% in nested cross validation) and the models were assembled by stacking with a simple majority vote and used for the virtual screening of over the “named” ZINC data set (over 100,000 compounds). 744 compounds were predicted by at least 50% of the QSAR models as active, 147 compounds were within the applicability domain and predicted by at least 75% of the models to be active. The latter 147 compounds were submitted to molecular ligand docking using Vina and Ledock, and a number of 90 were predicted to be active based on the binding energy. External data from CHEMBL and PUBCHEM confirmed that at least 7.83% (in the case of QSAR) or 6.67% (in the case of integrated QSAR and molecular docking) of the compounds are active on the c-src target.

show abstract

Combined inhibition of PI3K and Src kinases demonstrates synergistic therapeutic efficacy in clear-cell renal carcinoma

Cited by 12 publications

References 48 publications

Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction

Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction

Ex-Vivo Treatment of Tumor Tissue Slices as a Predictive Preclinical Method to Evaluate Targeted Therapies for Patients with Renal Carcinoma

Use of QSAR Global Models and Molecular Docking for Developing New Inhibitors of c-Src Tyrosine Kinase

Contact Info

Product

Resources

About