Therapeutic and prognostic implications of NOTCH and MAPK signaling in bladder cancer

Abstract

Signaling pathways that drive bladder cancer (BC) progression may be promising and specific targets for systemic therapy. Here, we investigated the clinical significance and targetability of NOTCH and mitogen‐activated protein kinase (MAPK) signaling for this aggressive malignancy. We assessed NOTCH1 and MAPK activity in 222 stage III and IV BC specimens of patients that had undergone radical cystectomy, and tested for clinical associations including cancer‐specific and overall survival. We examined therapeutic effects of NOTCH and MAPK repression in a murine xenograft model of human bladder cancer cells and evaluated tumor growth and tumor cell plasticity. In BC, NOTCH1 and MAPK signaling marked two distinct tumor cell subpopulations. The combination of high NOTCH1 and high MAPK activity indicated poor cancer‐specific and overall survival in univariate and multivariate analyses. Inhibition of NOTCH and MAPK in BC xenografts in vivo depleted targeted tumor cell subpopulations and revealed strong plasticity in signaling pathway activity. Combinatorial inhibition of NOTCH and MAPK signaling most strongly suppressed tumor growth. Our findings indicate that tumor cell subpopulations with high NOTCH and MAPK activity both contribute to tumor progression. Furthermore, we propose a new concept for BC therapy, which advocates specific and simultaneous targeting of these different tumor cell subpopulations through combined NOTCH and MAPK inhibition.

Impact of SOX2 function and regulation on therapy resistance in bladder cancer

“…Mitogen-activated protein kinase (MAPK) is widely expressed in multicellular organisms and has significant function in cell proliferation, differentiation, migration, and invasion ( 79 ). It can be classified into four subfamilies, namely, ERK, p38, JNK, and ERK5; each of these represents a pathway, with the ERK and JNK signaling pathways being the most deeply interconnected with BC ( 80 ). Hepburn et al.…”

RITA1 drives the growth of bladder cancer cells by recruiting TRIM25 to facilitate the proteasomal degradation of RBPJ

“…[13][14][15][16][17][18][19][20] Although inactivation of Notch signaling is associated with BC progression, the regulatory mechanism of Notch downstream targets remains unclear. [21][22][23][24][25] In this study, we identified a novel mechanism whereby overexpression of RITA1 drives the growth of BC cells by recruiting TRIM25 to ubiquitinate RBPJ and accelerate its proteasomal degradation, thus leading to the transcriptional inhibition of Notch1 downstream targets (Figure 6G).…”

Based on Bioinformatics Studies on the Effect of a lpha1H on Key Genes, Pathways in Bladder Cancer and lncRNA on Patient Prognosis

“…Signaling pathways associated with bladder cancer (BC) progression may be important targets for systemic therapy. Manal Elmasry et al [17] found that mitogen-activated protein kinase (MAPK / ERK) signaling is associated with BC progression, and the results showed that MAPK signaling can control BC cell activity, and that inhibition of M A P C signaling in BC xenografts would inhibit BC cell growth and reduce BC cell subsets. In this study, the genes signi cantly downregulated after treatment with the new drug alpha1H were associated with MAPK signaling.…”