Abstract PR16: Normal and neoplastic tissues with partial Hus1 impairment show hypersensitivity to cisplatin in vivo

The DNA damage response (DDR) factor HUS1 is vital for proper functioning of the ATR checkpoint pathway. Following DNA damage, HUS1 forms a heterotrimeric complex with RAD9 and RAD1 and works with other checkpoint and scaffold proteins to activate ATR and CHK1 kinases. HUS1 also has separate functions that promote DNA repair. Due to its essential nature and diverse roles in genome maintenance, we hypothesized that HUS1 would be critical in the response of normal and neoplastic tissues to the DNA-damaging chemotherapeutic, cisplatin. Cisplatin is a widely used chemotherapeutic that damages DNA via platinated adducts, which form intrastrand and interstrand crosslinks. To test our hypothesis, we made use of a mouse model whereby a hypomorphic Hus1 allele is combined with a null allele in order to achieve partial impairment (Hus1neo/1n) in vivo. Hus1+ and Hus1neo/1n FVB mice were administered high dose cisplatin intraperitoneally (13.5 mg/kg). Body weights were recorded daily and mice were euthanized when humane intervention criteria were met. Hus1neo/1n mice had reduced 7-day survival (P = .0071) and increased weight loss (P = .0485) when compared to Hus1+ mice. In order to determine if neoplastic tissues had a similar requirement for HUS1 in response to DNA damage inflicted by cisplatin, we combined Hus1 impairment with K-ras oncogene activation in vivo. K-RAS is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC). Mutations in this oncogene, the majority...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: DNA Damage Signaling: Oral Presentations - Proffered Abstracts Source Type: research