Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	22	5	2023 May 04	616-629	Mol Cancer Ther

URL

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
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
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
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
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
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