Most patients with advanced NSCLC don’t receive guideline recommended treatment as their poor performance status makes them ineligible for platin-based treatment protocols. While tumour-specific loss of ATM in early-resected NSCLC is associated with poor survival, these patients derive increased benefit from adjuvant chemotherapy, including cisplatin. We have previously reported that ATM-deficient cell lines in MCL and gastric cancer show increased sensitivity to PARP inhibition, and recent studies have indicated cisplatin sensitivity arising from DNA damage repair deficiencies. Here we present preclinical data suggesting that lower doses of platin in combination with PARP inhibition may be an option in patients whose tumours exhibit ATM loss.
We identified ATM-deficient NSCLC cell lines by protein expression and activation in response to ionizing radiation. Cells were treated with cisplatin and PARP inhibitor (olaparib) alone or in combinations to determine sensitivity by clonogenic survival assay. ATM was knocked out in an ATM-proficient cell line by Cas9-CRISPR gene editing, and cells were analyzed for the effect of cisplatin and olaparib on cell cycle progression.
ATM-deficient NSCLC cell lines were sensitive to both cisplatin and olaparib alone, and this effect was amplified when drugs were given in combination, even at lower doses of both. ATM signalling was activated in response to these drugs in ATM-proficient cells, however when ATM is knocked out the cells become more sensitive to either drug alone or in combination. Interestingly, apoptosis does not appear to increase in ATM-KO cells, but rather cells accumulate in G2 – particularly cells treated with olaparib.
Our results suggest that ATM loss is sufficient to sensitize NSCLC cells to combinations of cisplatin and olaparib. PARP inhibition may arrest cells in G2, and while cisplatin does not appear to push cells into an apoptotic state, cell death might be triggered via another mechanism. This suggests that NSCLC patients with ATM loss in their tumour may benefit from lower doses of platin and PARP inhibitors, a combination that may allow increased uptake of palliative systemic treatment including the addition of immunotherapy.
D. Gwyn Bebb.
Glans-Look Lung Cancer Research.
All authors have declared no conflicts of interest.