Vistusertib

Sunitinib remains the preferred systemic treatment option for specific patients with advanced RCC who are ineligible for immune therapy. However, it's essential to recognize that Sunitinib fails to elicit a favourable response in all patients. Moreover, most patients eventually develop resistance to Sunitinib. Therefore, identifying new targets associated with Sunitinib resistance is crucial. Utilizing multiple datasets from public cohorts, we conducted an exhaustive analysis and identified a total of 8 microRNAs and 112 mRNAs displaying significant expression differences between Sunitinib responsive and resistant groups. A particular set of six genes, specifically NIPSNAP1, STK40, SDC4, NEU1, TBC1D9, and PLAUR, were identified as highly significant via WGCNA. To delve deeper into the resistance mechanisms, we performed additional investigations using cell, molecular, and flow cytometry tests. These studies confirmed PLAUR's pivotal role in fostering Sunitinib resistance, both in vitro and in vivo. Our findings suggest that PLAUR could be a promising therapeutic target across various cancer types. In conclusion, this investigation not only uncovers vital genes and microRNAs associated with Sunitinib resistance in RCC but also introduces PLAUR as a prospective therapeutic target for diverse cancers. The outcomes contribute to advancing personalized healthcare and developing superior therapeutic strategies.

The PI3K–mTOR–AKT pathway regulates tumour proliferation, gene expression and metabolism, but pathway inhibition induces heterogeneous feedback reactivation, limiting anti-tumour responses. Measuring heterogeneity of pathway inhibition in tissues using protein biomarker phosphorylation or location is challenging. An integrated multi-modal imaging workflow was developed to assess the heterogeneity of AZD2014 (mTORC1/2 inhibitor) response in a PTEN-null renal cancer model. Spatial responses of metabolite biomarkers were analysed by mass spectrometry imaging (MSI). Control and treated tumours were classified according to metabolite-defined regions enriched in control versus AZD2014-treated tumours, respectively. Noticeably, AZD2014-treated tumours retained regions similar to regions dominant in untreated tumours. Imaging mass cytometry analysis of protein biomarkers in ‘control-like’ regions following AZD2014 treatment showed reduced phospho-S6, indicating suppression, but retained high expression of the glucose transporter GLUT1. Increasing PI3K–AKT inhibition by combining with AZD8186 (PI3Kβ inhibitor) further decreased the control-like metabolic signature, showing PI3K-dependent resistance. This demonstrates that MSI-based workflows yield novel insights into the pharmacodynamic effects of mTORC1/2 inhibition in tumours, which classical biomarkers do not resolve. Coupling these workflows with spatial-omics approaches can deliver greater insights into heterogeneity of treatment response.