Abstract 3848: Subtype-specific DNA damage dependent and independent functions of damage repair proteins confer chemo-resistance to leukemia

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-08, Vol.75 (15_Supplement), p.3848-3848
• Main Authors: Salunkhe, Sameer, Kaur, Ekjot, Ramaswamy, Ashwin, Patkar, Ketaki, Dutt, Shilpee
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2015-3848

Resistance to chemotherapy is a major challenge in the field of leukemia. Since, cancer cells can acquire resistance to DNA damage based therapy by modulating DNA Damage Repair (DDR) pathways, an in-depth understanding of DDR is important for novel drug discoveries. Hence, to understand relation between DDR and resistance we used doxorubicin resistant sub-line (K562-R) of K562 and Mitoxantrone resistant sub-line (HL60/MX) of HL60 as a model system. We show that lethal doses of Mitoxantrone to HL60 and HL60/MX do not induce DNA DSBs (double strand breaks) and accordingly there is no activation of Chk2, although there is equal uptake of drug in both, sensitive and resistant cell types. Since Mitoxantrone produce DSBs by targeting TOP2B, we checked the expression of TOPB2 and found significant decrease in the levels of topoisomerase 2 B (TOP2B). Moreover, negative regulator of TOPB2, mir 21-5P is upregulation in untreated HL60/MX explaining the absence of DSBs in HL-60/MX with Mitoxantrone treatment. Surprisingly, although there are no DSBs induced, we find high levels of DNA-PKcs, MRE11 and Rad50 in HL-60/MX. Furthermore, inhibition of DNA-PKcs re-sensitizes HL-60/MX cells to Mitoxantrone, suggesting a DNA damage independent role for DNA-PK in HL-60/MX cells. Recently DNA-PKcs is shown to play key role in fat metabolism. Indeed we find significant differences in the metabolism of HL60 and HL-60/MX where HL-60 cells use glucose but HL-60/MX cells show reduced glucose and glutamine metabolism and an over expression of fatty acid synthase. However link between DNA-PKcs over expression and differential metabolism in these cells still need to be explored. Interestingly, in contrast to HL60 model, Doxorubicin does induce equal DSBs in K562 and K562-R cells. However K562-R cells hyperactivate ATM and Chk2 to repair their DNA and survive. Importantly, we show that K562 start to show elevated activation of ATM and Chk-2 as early as two rounds of drug treatment. Accordingly, ATM inhibition leads to induction of apoptosis in resistant K562 cells. In conclusion, we show that K562 and HL60 cells use the DNA double strand break repair proteins in DNA damage dependent and independent pathways to acquire resistance to DSB inducing chemo therapeutics. Our data also highlight the importance of considering subtype specific therapeutics in leukemia. Note: This abstract was not presented at the meeting. Citation Format: Sameer Salunkhe, Ekjot Kaur, Ashwin Ramaswamy, Ketaki Patka