Browsing Over 138 Presentations
15P - ATM loss in NSCLC increases sensitivity to cisplatin and PARP inhibition (ID 191)
- D. Bebb
- D. Bebb
- L. Petersen
- J. Moore
- A. Elegbede
- S. Lees-Miller
Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Legal entity responsible for the study
D. Gwyn Bebb.
Funding
Glans-Look Lung Cancer Research.
Disclosure
All authors have declared no conflicts of interest.
Session DOI (ID 226)
Technical insights on liquid biopsies: Available techniques, sensitivity, GMP (ID 5)
- P. Laurent-Puig
- P. Laurent-Puig
Complex innovative designs (ID 38)
- Y. Shyr
- Y. Shyr
Cancer evolution as a therapeutic target (ID 111)
- A. Bardelli
- A. Bardelli
Q&A (ID 213)
- J. De Bono
- E. Calvo
- J. De Bono
- E. Calvo
Session DOI (ID 217)
Introduction: Making challenging marriages work (ID 29)
- T. Yap
- T. Yap
What editors (and authors) look for in good peer review (ID 94)
- A. Adjei
- A. Adjei
32P - Clinical correlation between different CKIT exon mutations and clinical outcome imatinib mesylate treatment in gastrointestinal stromal tumor (GIST) patients (ID 71)
- G. Zakaria
- G. Zakaria
- N. Allahloubi
- A. Bahnasy
- O. Khorshid
Abstract
Background
The clinical behavior of GISTs is highly variable. This study aims at detection of different histo-pathological tumor features and correlation with different clinical aspects after treatment with imatinib, based on C-KIT exon mutation status.
Methods
This is a retrospective study that included all cases diagnosed as GIST who presented to NCI from 2005 to 2017, The following data were collected from the patient’s files: age, gender, tumor site, size, mitotic rate, histological grade, capsular rupture, risk stratification by Joensuu criteria, treatment setting, date of start and end of treatment, dose and toxicity. KIT mutation was assessed on tumor tissues of all patients; clinical correlation between different clinical aspects after treatment with imatinib, based on C-KIT exon mutation status, was done.
Results
Eighty-nine cases of GIST presented to NCI in the period September 2005 to January 2017. Median age at diagnosis was 48 years old with a median follow up of 22 months. More than 75% of the patients had positive C-KIT mutation, while it was negative in 24.7 % of the patients. C-kit positive mutations were significantly associated with tumors more than 5 cm, high mitosis, and with high tumor risk stratification by Joensuu criteria in more than fifty percent of the patients. Exon 9 mutations had poor ORR (55.6 %) compared to those with exon 11(67.6%) (P = 0.33), with the latter having PFS of 55 months compared 120 months for exon 9 mutations, (P = 0.002). No statistically difference in OS was observed with exon 9 (70 months) compared to exon 11 mutations (77 months) (P = 0.55).
Conclusions
C-kIT-positive mutation per-se is an independent poor risk factor, associated with more aggressive tumor features whereas response to imatinib was affected by exon mutations with exon 11 having a tendency for better ORR, compared to exon 9 mutation, with the latter having longer PFS compared with exon 11, with no statistically difference in OS with exon 9 compared to exon 11 mutations.
Legal entity responsible for the study
NCI.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
BiTEs for cancer therapy (ID 20)
- R. Bargou
- R. Bargou
Introduction (ID 53)
- U. Banerji
- U. Banerji