• cancer

Aneuploidy is a common characteristic of cancer genomes and accelerates the development of anticancer drug resistance. Chromosomal instability (CIN) refers to the ongoing acquisition of genomic alterations that can involve either a gain or loss of whole chromosomes or structural aberrations, ranging from point mutations to small-scale genomic alterations and gross chromosomal rearrangements. CIN can be induced by defects that result in elevated DNA damage, weakened cell cycle checkpoints, or an aberrant mitotic spindle. Several models of CIN in Drosophila have been developed, using genes that affect these processes. Work in Drosophila is part of a growing effort to target CIN or to exploit downstream effects of CIN as therapeutic targets.

The most widely used Drosophila model targets the Dmel\mad2 gene, a conserved component of the spindle assembly checkpoint. RNAi-effected reduction in mad2 expression results in shortened mitoses and gives less time to correct any chromosome misorientation at metaphase II, resulting in a significantly higher rate of chromosome segregation errors. Other genes used to induce CIN include BubR1 (kinase with roles in spindle assembly checkpoint signalling and other aspects of mitosis and meiosis), Bub3 (also functions in the spindle assembly checkpoint (SAC) pathway), Rbf (several functions that impact genome stability), vtd (aka rad21, subunit of the cohesin complex), cmet (centrosome-associated kinesin-like motor protein), Kmn1 (component of a kinetochore complex), pnut (filament-forming cytoskeletal GTPase required for cytokinesis), Mps1 (a conserved protein kinase associated with kinetochores and required for the mitotic and meiotic spindle assembly checkpoints).

In the Drosophila mad2 model, CIN results in oxidative stress in aneuploid cells. Work exploiting this difference between normal and CIN cells resulted in identification of phosphoenolpyruvate carboxykinase (PEPCK) as a potential target. Proliferating CIN cells are shown to be vulnerable to inhibition of PEPCK (via RNAi or biochemical inhibitors), or its metabolic network, presumably because of their compromised redox status.

Several studies have made use of knockdown of the Bub3 gene combined with expression of BacA\p35, an inhibitor of apoptosis.

Cytokinesis failure, induced by RNAi directed against pnut, in combination with overexpression of the Hippo signaling pathway gene yki has been shown to result in neoplastic tumors. Using targeted expression in the wing, it has been demonstrated that cleavage defects trigger the activation of the JNK pathway, which leads to apoptosis, and that yki inhibits this tumor-suppressive role of JNK.

Reduced levels of pyridoxal 5'-phosphate (PLP, the active form of vitamin B6), induced by mutations in genes involved in PLP synthesis or by PLP inhibitors, have been shown to cause DNA damage and subsequent loss of heterozygosity. In a sensitive genotype (heterozygous for wts mutation) PLP inhibitors have been shown to induce the development of epithelial tumors. See also the human disease model report 'pyridoxamine 5'-phosphate oxidase deficiency' (FBhh0001037).

[updated Jun. 2022 by FlyBase; FBrf0222196]