Treatment of both <i>Tsc2<sup>+/</sup></i><sup>-</sup> mice and a TSC1-null bladder cancer xenograft model with a CDK7 inhibitor showed marked reduction in tumor volume and absence of regrowth in the xenograft model.
In addition, we observed that bladder cancer cell lines (RT4, UMUC-3, and J82) with homozygous deletion of either TSC1 or PTEN are more sensitive to metformin than those (TEU2, TCCSUP, and HT1376) with wild-type TSC1 and PTEN genes.
Despite the recent pivotal study evidencing specific mutations of TSC1 in bladder cancer patients responding to everolimus and the encouraging results obtained with other derivatives than rapalogs, few clinical trials are ongoing in bladder cancers.
The TSC1 c. 1907 1908 del (E636fs) mutation in bladder cancer suggests that the location of the mutation is Exon 15 with frequency of TSC1 mutation of 11.7 %.
Targeted sequencing revealed TSC1 mutations in about 8% of 109 additional bladder cancers examined, and TSC1 mutation correlated with everolimus sensitivity.
We conclude that although TSC1 missense mutations do not play a major role in causation of TSC disease, they represent a significant proportion of somatic loss of function mutations in bladder cancer.
Recent data suggest that functional inactivation of TSC proteins might also be involved in the development of other diseases not associated with TSC, such as sporadic bladder cancer, breast cancer, ovarian carcinoma, gall bladder carcinoma, non-small-cell carcinoma of the lung, and Alzheimer's disease.
This may indicate that haploinsufficiency for TSC1 can contribute to the development of bladder cancer and, if so, that the LOH of TSC1 observed in >50% of TCCs is biologically significant.