# Targeted Therapy in Metastatic Bladder Cancer: Present Status and Future Directions
## 5 MAPK and Pi3K/AKT/mTOR Pathway Alterations  
The MAPK and Pi3K/AKT/mTOR signaling cascades are activated by RTKs. Activation of MAPK and PI3K signaling cascades is a common finding in BC and promotes cell growth and survival [38]. These pathways show frequent crosstalk by sharing subunits and negative/positive feedback loops [38]. Activating mutations in RAS genes--HRAS (5%), KRAS (5%), or NRAS (2%)--are present in a minority of MIBC patients [9]. The Pi3K/Akt/mTOR pathway can also be directly activated by activating mutations in the phosphoinositide 3-kinase catalytic subunit alpha (PIK3 CA). Constitutively active PIK3 CA produces phosphatidylinositol-3-phosphate (PIP3), which activates downstream actors of the Pi3K/Akt/mTOR pathway. Approximately 22% of MIBC patients have such activating PIK3 CA mutations [8]. Other genes commonly mutated in the Pi3K/AKT/mTOR pathway are the tumor suppressor genes PTEN and TSC1. PTEN is a phosphatase that antagonizes Pi3K by breaking down PIP3 and is mutated in 3% of MIBC patients, while TSC1 inhibits the pathway further downstream and is mutated in 8% of MIBC patients [8]. The MAPK and Pi3K/AKT/mTOR pathways are interesting candidates for targeted therapy, as more than 25% of patients have alterations in one of these pathways. However, crosstalk between the MAPK and Pi3K/AKT/mTOR pathways and upstream RTKs provide cancer cells with effective mechanisms to escape treatment directed against one pathway via activation of the other [38; 39; 40; 41; 42; 43]. For example, cell lines upregulate EGFR expression to overcome a temporary decrease in MAPK signaling induced by FGFR inhibition [41]. In addition, downstream activation of the Pi3K/AKT/mTOR pathway has been described as a resistance mechanism to FGFR inhibition [40; 42; 43]. Thus, these findings prompt development of a method that produces a combined inhibition of the RTK-MAPK and RTK-Pi3K/AKT/mTOR pathways.  
A phase I study investigating the mTOR inhibitor everolimus combined with the vascular endothelial growth factor RTK (VEGFR) inhibitor pazopanib showed a favorable toxicity profile and clinical benefit was observed in 4 of 19 included patients with mUC harboring TSC1/TSC2 mutations [44]. Two PIK3 CA inhibitors are also included in the MATCH basket trial: copanlisib (BAY 80-6946) for patients with Pi3 KCA-activating mutations and or PTEN-inactivating mutations, and GSK2636771 for patients with PTEN-inactivating mutations (NCT02465060). The mTOR inhibitor sorafenibib was investigated in the neoadjuvant setting in combination with gem/cis and showed acceptable toxicity; furthermore, the ErbB family or MAPK pathway alterations were predictive of therapy response [45]. Sorafenib combined with vinflunine in platinum-relapsed mUC patients showed an impressive ORR of 41%, supporting further trials [46]. In summary, RTKs converge on the MAPK and Pi3K/AKT/mTOR pathways to drive MIBC. Crosstalk between these pathways provides UC cells with mechanisms of resistance to RTK inhibition. Treatment resistance could be overcome by either the combined inhibition of multiple RTKs at the same time or interference with the crosstalk between the two pathways in pre-clinical models. We are looking forward to subsequent clinical trials that evaluate the effect of FGFR and ErbB family inhibition by, for example, attainib + erdafitinib administered synchronously or in short intervals. Likewise, future clinical trials should consider FGFR or ErbB inhibition combined with Pi3K or mTOR inhibitors.