Mint3‐targeted therapy: A novel therapeutic strategy for urothelial carcinoma

Bladder cancer (BC) is the most common neoplasm of urinary system, which associated with high morbidity and mortality rates. Globally, 573 278 new cases 212 536 related deaths were reported in 2020.1 Urothelial carcinoma (UC) frequent histologic type among BC, 75% non-muscle-invasive BCs (NMIBCs) 25% MIBCs. The definition UC urothelial-origin neoplastic cells that invade basement membrane, lamina propria, or deeper. NMIBCs frequently recur progress to MIBCs,2 are usually lower 5-year survival rates, progression, metastasis.3 Kinds driver events aberrantly activated UC. In this issue Clinical Translational Medicine, Ikeda et al. demonstrated Mint3 responsible for poor prognosis UC, as both deletion inhibition would hinder tumour development.4 Mechanistically, a positive regulator hypoxia-inducible factor-1 (HIF-1), highly diversified oncogenic processes cells, such angiogenesis, glycolysis, motility, invasion (Figure 1). Mutations two genes, namely FGFR3 TP53, generally recognized pathological process former mainly comprises papillary low-grade tumours arising from localized flat urothelial hyperplasia accompanied by only single few genetic alterations.5 Different FGFR3-mutated TP53 mutation-related ones defined essential situ (CIS) developed severe dysplasia consist non-papillary high-grade tumours. TP53-mutated considerably more lethal due its rate progression association multiple chromosomal abnormalities muscle-invasive tumours.6 Meanwhile, certain gene mutations observed confirmed non-muscle but similar molecular alterations CIS, results prognosis.7 protocol treatment was built 20 years ago has proved be efficient overall benefits ever since.8 However, longstanding paradigm been challenged supplemented therapies emerged recently, including immuno-checkpoint inhibitors,9 antibody-drug conjugates (ADCs),10 novel targeted drugs.11 general, platinum-based chemotherapy recommended first-line standard therapy suitable patients, while cisplatin preferred carboplatin. Immuno-checkpoint could an alternative if PD-L1 status patient positive. Immunotherapy commonly used second-line treatment, some integrated into chemotherapy, appropriate patients applying therapies. several trials Nectin-4 ADC FGFR inhibitors solely combined different chemotherapies undergoing. updated drugs listed Table 1. Among all biological pathways, MAPK/PI3K-HIF1 signalling pathway contribute significantly pathologies participating UC-associated tumourigeneses metastasis processes, cell proliferation, apoptosis, angiogenesis.23 HIF-1 member basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) protein family heterodimer consisting HIF-1α HIF-1β subunits. degrades under nonmonic conditions stable hypoxic functions master transcriptional adaptive response hypoxia, whereas latter expressed constitutively.24 wildly involved numerous types cancers. Significant associations between overexpression have cancers brain, breast, cervix, oropharynx, ovary, uterus.25 case, often upregulated early advanced stages Several studies delineated activation predicts prognosis, accelerates growth promotes radiation resistance upregulating carcinogenic knockout quenches promoting roles.25-27 Although it seems promising develop HIF-1-targeted drug ideal strategy therapy, difficulties arose, no inhibitor clinically available date result, despite countless efforts applied during last decade search potential inhibitors.23 Another divert attention regulators. Along illustrious translation points like PI3K mTOR, newly discovered activator. It exhibits lines.28, 29 other members X11 family, Mint1 Mint2, neuron proteins, Munc18-1-interacting 3 (Mint3/X11γ/APBA3) ubiquitously tumours.30 activity typically regulated factor inhibiting (FIH-1), asparaginyl hydroxylase functioning interrupter preventing binding co-factor p300/CBP modifying Asn803 residue HIF-1α. capable competitively FIH-1 through N-terminal region, thus HIF-1α.31 protein-protein interaction FIH1 also regarded key regulatory mechanism Warburg effect, one phenomena considered play pivotal role proliferation cells.30 lead enhancement chemosensitivity kinds malignancies, breast cancer, pancreatic lung fibrosarcoma.29, 32-34 Unlike concentration fervency research discovery, there acknowledged antagonists unclearness regulating mode FIH-1. Inspiringly, recent works focusing on structure revealed basis identified amino acids 78 88 region FIH-1.30 These findings than likely accelerate development Mint3-targeted Besides Mint3-HIF-1 axis Ikeda's work highlighted antagonistic function drug, naphthofluorescein, against chemoresistance. This bring current reasonable countermeasures caused long-term chemotherapies, especially treatments still requires abundant investigations effectiveness ineluctable side effect materialize clinical vision, given microenvironment heterogeneity complexity HIF-1. We acknowledge technical support Core utilities genomics pathobiology department anatomical cellular pathology, Chinese University Hong Kong. authors declare they conflict interest.