Positive regulatory loop of platelet-derived growth factor DD-induced STAT3 activation is associated with poor prognosis in advanced urothelial carcinoma

Kiyohiro Ando; Ryo Kurashina; Noriko Motoi; Toshihiko Iizuka; Masaharu Inoue; Riko Maruyama; Kouki Mitani; Hisanori Takenobu; Masayuki Haruta; Ritsuko Onuki; Yoh Matsuoka; Takehiko Kamijo; Yukio Kageyama

doi:10.1016/j.bbrc.2023.07.054

Positive regulatory loop of platelet-derived growth factor DD-induced STAT3 activation is associated with poor prognosis in advanced urothelial carcinoma

Biochem Biophys Res Commun. 2023 Oct 8:676:165-170. doi: 10.1016/j.bbrc.2023.07.054. Epub 2023 Jul 26.

Authors

Affiliations

¹ Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina, Kita-adachigun, Saitama, 362-0806, Japan. Electronic address: kiyohiro_ando@saitama-pho.jp.
² Department of Urology, Saitama Cancer Center, 780 Komuro, Ina, Kita-adachigun, Saitama, 362-0806, Japan.
³ Department of Pathology, Saitama Cancer Center, 780 Komuro, Ina, Kita-adachigun, Saitama, 362-0806, Japan.
⁴ Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina, Kita-adachigun, Saitama, 362-0806, Japan.

PMID: 37517219
DOI: 10.1016/j.bbrc.2023.07.054

Abstract

Immune checkpoint inhibitor (ICI) therapy has been established for patients with advanced urothelial cancer (UC). The necessity of overcoming resistance to ICIs and identifying a predictive factor for the same has been highlighted, such as the assessment of combination therapy with other targeted drugs and the characterization of molecular signatures in the tumor microenvironment. Recently, we reported that low hemoglobin (Hb) levels and a high platelet-to-lymphocyte ratio (PLR) were significantly associated with overall survival in patients with UC who did not benefit from pembrolizumab treatment. In the present study, we identified a possible link between these unfavorable prognostic indicators and PDGF-DD-induced STAT3 activation in UC. Overlapping patients between the high STAT3- or phosphorylated STAT3-positive score group (as assessed by immunohistochemistry) and low Hb levels or high PLR group (as assessed by blood tests) showed significantly worse outcomes after pembrolizumab treatment. Additionally, using the bladder cancer JMSU1 cell line, we demonstrated a possible positive regulatory loop between autocrine/paracrine PDGF-DD and STAT3 signaling. Therefore, we suggest that STAT3 inhibition and PDGF-DD detection in the tumor microenvironment might represent a potential therapeutic strategy to overcome resistance to pembrolizumab. Moreover, this can help identify patients with UC who could benefit from combination treatment.

Keywords: Bladder cancer; PDGFD; Pembrolizumab; Platelet-to-lymphocyte ratio; STAT3; Urothelial cancer.