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J. Moore
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-100 - Platin-Induced ATM Activation in Non-Small Cell Lung Cancer (ID 2984)
09:30 - 09:30 | Author(s): J. Moore
- Abstract
Background:
Platinum based antineoplastic therapies (platins) are a first line treatment prescribed for non-small cell lung cancer (NSCLC), but unfortunately have many adverse side effects. Cytotoxicity is caused by the generation of DNA adducts, which create single and double stranded DNA breaks and stimulate DNA damage response pathways. A key mediator of this response is ataxia telangiectasia mutated (ATM), which is responsible for the activation of several downstream targets involved in DNA repair, cell cycle arrest, and apoptosis. Of great interest are platin sensitivity markers that help identify patients more susceptible to these treatments. Previous research on predictive markers of platin sensitivity has focused on ERCC1 and RRM1 with varying levels of success. Our lab has shown that cells lacking ATM have increased sensitivity to some platin therapies. We hypothesize that ATM signaling may be invoked by platin exposure and that tumours deficient in ATM may have innate sensitivity to platin therapies. Here we assess the molecular action of ATM in response to different platin therapies to determine whether low activity in ATM-deficient cells is predictive of platin sensitivity.
Methods:
Six NSCLC cell lines were assessed for the presence of ATM by western blot. Those cell lines for which ATM was not found were deemed ATM-deficient. Cell lines were treated with varying concentrations of platinum based therapies (cisplatin, carboplatin and oxaloplatin) for two hours or overnight. ATM activation was determined by assessment of phosphorylated-ATM protein levels using western blots. Additionally, downstream targets of ATM were probed to determine ATM pathway activation.
Results:
NSCLC cell lines H226, H460 and H522 were found to be ATM-proficient whereas cell lines H23, H1373 and H1395 were found to be ATM-deficient. ATM-proficient cell lines demonstrated an increased level of phosphorylated-ATM in response to treatments with cisplatin, carboplatin, and oxaliplatin. In addition, downstream targets of ATM also showed increased levels of activation when compared to non-treated controls. ATM-deficient cell lines showed no increased levels of phosphorylated-ATM however, downstream targets of ATM showed some activation in ATM-deficient cell lines.
Conclusion:
We have shown that cisplatin, carboplatin and oxaliplatin treatments induce the phosphorylation of ATM, a prominent regulator of the DNA damage response. In addition, the ATM-deficient cell lines showed reduced activation of ATM to platin treatments. It is clear that platin exposure induced an ATM mediated signalling response, however its predictive capabilities of platin sensitivity is still unclear. Activation of DNA repair by platins may leave ATM-deficient tumours at a disadvantage when mounting repair responses to these treatments. This data suggests that individuals with low or non-functioning ATM may be candidates for precision low-dose therapies that exploit this deficiency.
