# SEA and GATOR 10 Years Later
## 8 GATOR in Human Diseases
### Cancer and Anticancer Drug Resistance--NPRL2 and Others  
Among GATOR1 components, NPRL2 was the first that was suggested to be a tumor suppressor [195] almost a decade before the GATOR1 complex was described for the first time. NPRL2 has the higher cancer-associated recurrent mutational frequency out of all the GATOR1 genes [173]. For example, missense mutations in metastatic breast cancers are twice more frequent in Nprl2 (1.55%), than in Nprl3 or Depdc5 (0.78%) [196]. Low levels of NPRL2 expression have mostly been detected in solid tumors (Figure 6), including hepatocellular carcinoma [197], glioblastoma [12], as well as in renal [198,199], ovarian [12,199], colorectal [199,200,201, 202], breast [199,203] and lung cancers [157,160,199,204, 205]. Paradoxically, NPRL2 might also have functions as an oncogene. Recent studies in castration resistant prostate cancer (CRPC) revealed that poor prognosis is associated with high expression of NPRL2 [206].  
Alternations of NPRL2 expression is also related to the resistance to a number of anticancer drugs. The most recurrent cases are associated with the resistance to cisplatin and doxorubicin, which has been initially observed in Npr2 deletion mutants in yeast [156] and further confirmed in human lung cancer cell lines [157,160]. The reason of this resistance is still not clear, but it could be related with a role of NPRL2 in DNA damage response (see above) [54,160]. Overexpression of NPRL2 in colon cancer cells increases the sensitivity to a topoisomerase I inhibitor irinotecan (CPT-11) by activation of the DNA damage checkpoints [207]. Genomic alternations of all three GATOR1 components have recently been associated with the resistance to PI3K\(\alpha\) inhibitors in primary and metastatic breast cancer [208]. This resistance is explained by the sustained activation of the mTOR1 pathway due to the loss of function mutations of GATOR1 components. In this case, it is reasonable to expect that concomitant mTOR blockage by rapalogs or mTOR pan-inhibitors might overcome resistance. Inversely, CRPC cells, where NPRL2 expression is elevated, are resistant to everolimus [209].  
Surprisingly, during the last decade, not a single article reported a study about the involvement of NPRL3 in cancer and drug resistance, even if in the COSMIC database there are almost three times more somatic cancer mutations listed for NPRL3 than for its paralogue NPRL2.  
A low frequency DEPDC5 inactivation mutation has been observed in glioblastoma and ovarian cancer, but was not further investigated [12]. DEPDC5 downregulation was also observed in tumors of breast cancer patients [53], where it is strongly correlated with the upregulation of KLHL22 E3-ubiquitin ligase, responsible for DEPDC5 polyubiquity-lation and degradation (see above). Recently, DEPDC5 inactivation was discovered in gastrointestinal stromal tumors (GIST), one of the most common human sarcomas. Chromosome 22q deletions are observed in \(\sim\)50% of GIST and recurrent genomic inactivation of DEPDC5 (>16%) makes it the bona-fide tumor suppressor contributing to GIST progression via increased mTOR1 pathway signaling [210]. This is in striking contrast with >250 non-GIST sarcomas where DEPDC5 aberrations are infrequent (\(\sim\)1%). Interestingly, cancer occurrence in epilepsy probands with germline GATOR1 variants is very low and at present it is considered that there is no link between epileptic germline GATOR1 variants and cancer [181].  
Currently, >2000 somatic mutations in different tumors are listed for GATOR1 genes in the COSMIC database, none of them have been studied in detail. It is reasonable to expect that in the following years we should gain more information about the molecular mechanisms associated with the tumorogenesis provoked by these mutations.