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Ref Type Journal Article
PMID (36805958)
Authors Marqués M, Corral S, Sánchez-Díaz M, Del Pozo N, Martínez de Villarreal J, Schweifer N, Zagorac I, Hilberg F, Real FX
Title Tumor and Stromal Cell Targeting with Nintedanib and Alpelisib Overcomes Intrinsic Bladder Cancer Resistance.
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Abstract Text Bladder cancer is a highly prevalent tumor, requiring the urgent development of novel therapies, especially for locally advanced and metastatic disease. Nintedanib is a potent antifibrotic angio-kinase inhibitor, which has shown clinical efficacy in combination with chemotherapy in patients with locally advanced muscle-invasive bladder cancer. Nintedanib inhibits fibroblast growth factor receptors (FGFRs), validated targets in patients with bladder cancer harboring FGFR3/2 genetic alterations. Here, we aimed at studying its mechanisms of action to understand therapy resistance, identify markers predictive of response, and improve the design of future clinical trials. We have used a panel of genetically well-characterized human bladder cancer cells to identify the molecular and transcriptomic changes induced upon treatment with nintedanib, in vitro and in vivo, at the tumor and stroma cell levels. We showed that bladder cancer cells display an intrinsic resistance to nintedanib treatment in vitro, independently of their FGFR3 status. However, nintedanib has higher antitumor activity on mouse xenografts. We have identified PI3K activation as a resistance mechanism against nintedanib in bladder cancer and evidenced that the combination of nintedanib with the PI3K inhibitor alpelisib has synergistic antitumor activity. Treatment with this combination is associated with cell-cycle inhibition at the tumoral and stromal levels and potent nontumor cell autonomous effects on α-smooth muscle actin-positive tumor infiltrating cells and tumor vasculature. The combination of nintedanib with PI3K inhibitors not only reversed bladder cancer resistance to nintedanib but also enhanced its antiangiogenic effects.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA E542Q PIK3CA E674Q urinary bladder cancer sensitive Nintedanib + Pictilisib Preclinical - Cell culture Actionable In a preclinical study, combination treatment with Ofev (nintedanib) and Pictilisib (GDC-0941) inhibited cell proliferation in a bladder cancer cell line harboring PIK3CA E542Q and PIK3CA E674Q in culture (PMID: 36805958). 36805958
PIK3CA E542Q PIK3CA E674Q urinary bladder cancer sensitive Alpelisib + Nintedanib Preclinical - Cell line xenograft Actionable In a preclinical study, combination treatment with Ofev (nintedanib) and Piqray (alpelisib) led to synergistic inhibition of growth in bladder cancer cell lines harboring PIK3CA E542Q and PIK3CA E674Q in culture, and led to inhibition of tumor growth in a cell line xenograft model (PMID: 36805958). 36805958
FGFR3 K652E PIK3CA P124L urinary bladder cancer sensitive Nintedanib + Pictilisib Preclinical - Cell culture Actionable In a preclinical study, combination treatment with Ofev (nintedanib) and Pictilisib (GDC-0941) inhibited cell proliferation in a bladder cancer cell line harboring FGFR3 K652E PIK3CA P124L in culture (PMID: 36805958). 36805958
FGFR3 K652E PIK3CA P124L urinary bladder cancer sensitive Alpelisib + Nintedanib Preclinical - Cell culture Actionable In a preclinical study, combination treatment with Ofev (nintedanib) and Piqray (alpelisib) led to synergistic inhibition of growth in a bladder cancer cell line harboring FGFR3 K652E and PIK3CA P124L in culture (PMID: 36805958). 36805958
FGFR3 R248C PIK3CA A1066V urinary bladder cancer sensitive Nintedanib + Pictilisib Preclinical - Cell culture Actionable In a preclinical study, combination treatment with Ofev (nintedanib) and Pictilisib (GDC-0941) inhibited cell proliferation in a bladder cancer cell line harboring FGFR3 R248C and PIK3CA A1066V in culture (PMID: 36805958). 36805958