In Vitro and In Silico Analysis of Epithelial-Mesenchymal Transition and Cancer Stemness as Prognostic Markers of Clear Cell Renal Cell Carcinoma

Sharma, Revati; Balta, Showan; Raza, Ali; Escalona, Ruth; Kannourakis, George; Prithviraj, Prashanth; Ahmed, Nuzhat

doi:10.3390/cancers15092586

Cited by 5 publications

(2 citation statements)

References 85 publications

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“…Despite good initial responses, most patients with metastatic ccRCC develop resistance to SoC agents (20,21). Increased expression of Bcl-2 pro-survival factors like MCL1 and BCLxL have previously been described as resistance mechanisms to ccRCC SoC agents like TKIs, and mTORCi (34,35).…”

Section: Mcl1 Inhibition Synergizes With Standard Of Care Agents In P...mentioning

confidence: 99%

“…For patients with metastatic ccRCC, approved therapies include cytokine therapy, tyrosine kinase inhibitors (TKIs), HIF2a inhibitors, anti-angiogenesis agents and immune checkpoint blockade (18,19). Despite favorable initial responses, most patients relapse and present with drug resistant disease (20,21). For these patients, there remains an urgent unmet need to develop novel targeted agents.…”

Section: Introductionmentioning

confidence: 99%

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PBRM1 loss is associated with increased sensitivity to MCL1 and CDK9 inhibition in clear cell renal cancer

Fultang,

Schwab,

McAneny-Droz

et al. 2024

Front. Oncol.

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MCL1 is a member of the BCL2 family of apoptosis regulators, which play a critical role in promoting cancer survival and drug resistance. We previously described PRT1419, a potent, MCL1 inhibitor with anti-tumor efficacy in various solid and hematologic malignancies. To identify novel biomarkers that predict sensitivity to MCL1 inhibition, we conducted a gene essentiality analysis using gene dependency data generated from CRISPR/Cas9 cell viability screens. We observed that clear cell renal cancer (ccRCC) cell lines with damaging PBRM1 mutations displayed a strong dependency on MCL1. PBRM1 (BAF180), is a chromatin-targeting subunit of mammalian pBAF complexes. PBRM1 is frequently altered in various cancers particularly ccRCC with ~40% of tumors harboring damaging PBRM1 alterations. We observed potent inhibition of tumor growth and induction of apoptosis by PRT1419 in various preclinical models of PBRM1-mutant ccRCC but not PBRM1-WT. Depletion of PBRM1 in PBRM1-WT ccRCC cell lines induced sensitivity to PRT1419. Mechanistically, PBRM1 depletion coincided with increased expression of pro-apoptotic factors, priming cells for caspase-mediated apoptosis following MCL1 inhibition. Increased MCL1 activity has been described as a resistance mechanism to Sunitinib and Everolimus, two approved agents for ccRCC. PRT1419 synergized with both agents to potently inhibit tumor growth in PBRM1-loss ccRCC. PRT2527, a potent CDK9 inhibitor which depletes MCL1, was similarly efficacious in monotherapy and in combination with Sunitinib in PBRM1-loss cells. Taken together, these findings suggest PBRM1 loss is associated with MCL1i sensitivity in ccRCC and provide rationale for the evaluation of PRT1419 and PRT2527 for the treatment for PBRM1-deficient ccRCC.

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Section: Mcl1 Inhibition Synergizes With Standard Of Care Agents In P...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PBRM1 loss is associated with increased sensitivity to MCL1 and CDK9 inhibition in clear cell renal cancer

Fultang,

Schwab,

McAneny-Droz

et al. 2024

Front. Oncol.

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Effective Targeting of Colorectal Cancer Stem Cells by Inducing Differentiation Mediated by Low‐Dose Vitamin C via β‐Catenin Retention in the Cell Membrane

Shanavas,

Sen,

Banerjee

et al. 2024

J of Cellular Biochemistry

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Cancer stem cells (CSCs) are implicated as the underlying cause of tumor recurrence due to their refractoriness to conventional therapies. Targeting CSCs through novel approaches can hinder their survival and proliferation, potentially reducing the challenges associated with tumor relapse. Our previous study demonstrated that colorectal cancer stem cells (CR‐CSCs) showed sensitivity to Vitamin C (Vit C), displaying a dose‐responsive effect where low doses (2–10 µM) promoted cell proliferation while high doses induced cell death. In this study, we unraveled the mechanistic effects of low doses that, although induced proliferation, remarkably facilitated stemness reduction in HT‐29 cell line‐derived CR‐CSCs. Our findings revealed that Vit C doses of 2 and 6 µM resulted in a reduction in stemness as evidenced by a reduced CD44+ cell population, representing CR‐CSCs. The key finding was the remarkable increase in the expression of β‐catenin protein following low‐dose Vit C treatment, despite a reduction in stemness, accompanied by a mesenchymal to epithelial transition (MET). The sequestration of upregulated β‐catenin via E‐cadherin to the cell membrane was identified as a mechanism for reduced stemness, MET, and differentiation of CR‐CSCs. Importantly, the epithelial phenotype induced by low‐dose Vit C rendered CR‐CSCs sensitive to conventional treatments, enhancing chemosensitivity to Cisplatin, Paclitaxel, and 5‐Fluorouracil by 60%–90%. These findings suggest that low dose Vit C could serve as an adjuvant to conventional therapeutic strategies for targeting advanced colorectal cancer by sensitizing CR‐CSCs to chemotherapy and potentially reducing tumor recurrence.

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Tumor‐Specific Nano‐Herb Delivery System with High L‐Arginine Loading for Synergistic Chemo and Gas Therapy against Cervical Cancer

Chen,

Ming,

et al. 2024

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Cancer metastasis poses significant challenges in current clinical therapy. Osthole (OST) has demonstrated efficacy in treating cervical cancer and inhibiting metastasis. Despite these positive results, its limited solubility, poor oral absorption, low bioavailability, and photosensitivity hinder its clinical application. To address this limitation, a glutathione (GSH)‐responded nano‐herb delivery system (HA/MOS@OST&L‐Arg nanoparticles, HMOA NPs) is devised for the targeted delivery of OST with cascade‐activatable nitric oxide (NO) release. The HMOA NPs system is engineered utilizing enhanced permeability and retention (EPR) effects and active targeting mediated by hyaluronic acid (HA) binding to glycoprotein CD44. The cargoes, including OST and L‐Arginine (L‐Arg), are released rapidly due to the degradation of GSH‐responsive mesoporous organic silica (MOS). Then abundant reactive oxygen species (ROS) are produced from OST in the presence of high concentrations of NAD(P)H quinone oxidoreductase 1 (NQO1), resulting in the generation of NO and subsequently highly toxic peroxynitrite (ONOO−) by catalyzing guanidine groups of L‐Arg. These ROS, NO, and ONOO− molecules have a direct impact on mitochondrial function by reducing mitochondrial membrane potential and inhibiting adenosine triphosphate (ATP) production, thereby promoting increased apoptosis and inhibiting metastasis. Overall, the results indicated that HMOA NPs has great potential as a promising alternative for the clinical treatment of cervical cancer.

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In Vitro and In Silico Analysis of Epithelial-Mesenchymal Transition and Cancer Stemness as Prognostic Markers of Clear Cell Renal Cell Carcinoma

Cited by 5 publications

References 85 publications

PBRM1 loss is associated with increased sensitivity to MCL1 and CDK9 inhibition in clear cell renal cancer

PBRM1 loss is associated with increased sensitivity to MCL1 and CDK9 inhibition in clear cell renal cancer

Effective Targeting of Colorectal Cancer Stem Cells by Inducing Differentiation Mediated by Low‐Dose Vitamin C via β‐Catenin Retention in the Cell Membrane

Tumor‐Specific Nano‐Herb Delivery System with High L‐Arginine Loading for Synergistic Chemo and Gas Therapy against Cervical Cancer

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