Mutational inactivation of mTORC1 repressor gene DEPDC5 in human gastrointestinal stromal tumors

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common human sarcoma and are initiated by activating mutations in the KIT or PDGFRA receptor tyrosine kinases. Chromosome 22q deletions are well-recognized frequent abnormalities in GISTs, occurring in ∼50% of GISTs. These deletions are thought to contribute to the pathogenesis of this disease via currently unidentified tumor suppressor mechanisms. Using whole exome sequencing, we report recurrent genomic inactivated DEPDC5 gene mutations in GISTs (16.4%, 9 of 55 patients). The demonstration of clonal DEPDC5 inactivation mutations in longitudinal specimens and in multiple metastases from individual patients suggests that these mutations have tumorigenic roles in GIST progression. DEPDC5 inactivation promotes GIST tumor growth in vitro and in nude mice. DEPDC5 reduces cell proliferation through the mTORC1-signaling pathway and subsequently induces cell-cycle arrest. Furthermore, DEPDC5 modulates the sensitivity of GIST to KIT inhibitors, and the combination therapy with mTOR inhibitor and KIT inhibitor may work better in GIST patients with DEPDC5 inactivation. These findings of recurrent genomic alterations, together with functional data, validate the DEPDC5 as a bona fide tumor suppressor contributing to GIST progression and a biologically relevant target of the frequent chromosome 22q deletions.

<p>The Use of Molecular Subtypes for Precision Therapy of Recurrent and Metastatic Gastrointestinal Stromal Tumor</p>

“…121 Recently, Pang et al found that DEPDC5 was a GIST-specific tumor suppressor and TKI treatment response regulator, and was closely related to the development and progression of GISTs. 122 Sequencing of the entire exon showed that DEPDC5 reduced cell proliferation and induced cell cycle arrest through the mTORC1 signaling pathway, but it could lead to the progression of GISTs when it lost function due to inactivation mutation. In addition, DEPDC5 is not only a potential therapeutic target, but also can regulate the sensitivity of GISTs to KIT inhibitors.…”

FOXL2 homozygous genotype and chromosome instability are associated with recurrence in adult granulosa cell tumors of the ovary

“…The SMARCB1/INI1 gene was identified as a potent tumor suppressor in rhabdoid tumors, epithelioid sarcomas, schwannomatosis, synovial sarcomas, and other conditions [17]. Recently, Pang et al reported recurrent genomic inactivated DEPDC5 mutations in GISTs; the mutations were prognostic in that they were associated with aggressive GISTs, GIST progression, and low sensitivity to KIT inhibitors [18]. The loss of tumor suppressor genes in 22q region has yet to be reported in aGCTs.…”

Genomic Alterations in PIK3CA-Mutated Breast Cancer Result in mTORC1 Activation and Limit the Sensitivity to PI3Kα Inhibitors

“…The GATOR1 (26) and KICSTOR (33,34) complexes are negative regulators of mTORC1 activity in the amino acid sensing pathway, which is a key branch within the mTOR network. Mutational inactivation or decreased expression levels of DEPDC5 or NPRL2 have been reported in glioblastoma, ovarian cancer, and gastrointestinal stromal cancer (26,40,41). Loss of GATOR1 complex, the GAP for RagA or RagB, via DEPDC5, NPRL2 or NPRL3 KO should increase levels of GTP-bound RagA or RagB and, therefore, lead to constitutive activation of mTOR (26).…”