Targeting chromosomal instability for the specific killing of cancer cells

© 2013 Dr. Heidi Wing Shuen WongChromosomal INstability (CIN), a common feature of advanced tumors, is linked to drug resistance, metastasis, relapse and lower survival rates of patients in clinical settings. CIN describes cells with the tendency to progressively gain and lose large sections of DNA. This feature is often observed in cells with defects in chromosomal segregation, a process monitored by the spindle assembly checkpoint (SAC). Using Drosophila melanogaster carrying a weakened SAC as a CIN model, a genetic screen was carried out to identify genes that induce lethality specifically in animals with CIN. From this screen the c-Jun N terminal kinase (JNK) pathway was identified as a modifier of CIN cell fate. Knockdown of the JNK pathway was found to induce apoptosis in CIN but not normal cells, via the canonical apoptotic pathway, partly independent of the key tumor suppressor p53. Knockdown of SAC induces DNA damage, and the level of damage significantly increased when JNK was concurrently knocked down, implicating DNA damage in the induction of the observed apoptosis. Evidence is presented implicating G2 phase length in the survival of CIN cells, where shortening G2 but not G1 phase in CIN cells mimics the apoptosis induced by knockdown of JNK, while lengthening G2 but not G1 phase rescues the apoptosis. Based on these observations, I propose that JNK may therefore play a role in the regulation of G2 length following chromosome missegregation