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Transient receptor protein (TRP) channels are frequently associated with tumors and are correlated to patient’s outcome. We firstly investigated TRP channel melastatin 8 (TRPM8) expression in urothelial carcinoma of bladder (UCB) and its correlation with UCB clinicopathological features and additionally evaluated the association between TRPM8 expression and patients’ survival rate to elucidate its role in bladder oncogenesis. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was conducted to examine TRPM8 messenger RNA (mRNA) expression in 36 pairs of freshly frozen UCB tissues and matched noncancerous tissues. Immunohistochemistry (IHC) was performed in 156 archived paraffin-embedded UCB samples to explore the correlation between TRPM8 protein and clinicopathological features. The association between TRPM8 expression and patient’s survival rate was evaluated using the Kaplan–Meier method and multivariate Cox regression analysis, respectively. The expression levels of TRPM8 mRNA in UCB tissues were significantly higher than those in matched noncancerous tissues (P = 0.016). Expression of TRPM8 protein in UCB was significantly and positively associated with histological grade (P = 0.039) and tumor stage (P = 0.037). Significant correlation between high TRPM8 expression and poor cumulative survival of UCB patients was shown using the Kaplan–Meier survival curve (P = 0.039). TRPM8 was represented as an independent prognostic biomarker for UCB patients by multivariate Cox regression analysis (P = 0.047). The present study provide the convincing evidence for the first time that over-expression of TRPM8 may play a role in the pathogenesis and progression of UCB, and TRPM8 may serve as an independent prognostic biomarker for UCB patients.

Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive leukemia, but fail to explain many cases of clinical TKI failure. In contrast, it is largely unknown why some patients fail TKI therapy despite continued suppression of BCR-ABL1 kinase activity, a situation termed BCR-ABL1 kinase-independent TKI resistance. Here, we identified activation of signal transducer and activator of transcription 3 (STAT3) by extrinsic or intrinsic mechanisms as an essential feature of BCR-ABL1 kinase-independent TKI resistance. By combining synthetic chemistry, in vitro reporter assays, and molecular dynamics-guided rational inhibitor design and high-throughput screening, we discovered BP-5-087, a potent and selective STAT3 SH2 domain inhibitor that reduces STAT3 phosphorylation and nuclear transactivation. Computational simulations, fluorescence polarization assays and hydrogen–deuterium exchange assays establish direct engagement of STAT3 by BP-5-087 and provide a high-resolution view of the STAT3 SH2 domain/BP-5-087 interface. In primary cells from chronic myeloid leukemia (CML) patients with BCR-ABL1 kinase-independent TKI resistance, BP-5-087 (1.0 μM) restored TKI sensitivity to therapy-resistant CML progenitor cells, including leukemic stem cells. Our findings implicate STAT3 as a critical signaling node in BCR-ABL1 kinase-independent TKI resistance, and suggest that BP-5-087 has clinical utility for treating malignancies characterized by STAT3 activation.