Abstract 1951P
Background
Despite the advancement in new therapies in colorectal cancer (CRC), chemotherapy still constitutes the mainstay of the treatment. Poly-ADP-Ribose Polymerase inhibitors (PARPi) have the potential to increase the activity of DNA damaging chemotherapeutics such as 5-fluorouracil (5FU), oxaliplatin and irinotecan, even if dose-limiting toxicities have emerged at the currently used doses in previous clinical trials in molecularly unselected CRC patients.
Methods
We tested the combination of the PARPi niraparib (MK-4827) with either 5-fluorouracil, oxaliplatin or irinotecan (SN38) in a panel of 12 molecularly annotated CRC cell lines, encompassing the 4 consensus molecular subtypes (CMSs). Synergism was calculated using the Chou-Talalay method for drug interaction. A correlation between synergism and genetic alterations in genes involved in homologous recombination (HR) repair was performed. We used clonogenic assays, mice xenograft models and patient-derived 3D spheroids to validate the results. The induction of DNA damage was studied by immunofluorescence.
Results
Irinotecan/SN38 is the best candidate for combination with niraparib, showing strong synergism is 6/12 cell lines. Synergism was independent from CMS and microsatellite status. Strong synergistic activity of low-dose combinations of SN38 and niraparib was found in cell lines carrying a pathogenic mutation in ATM by induction of DNA double strand breaks. The strong activity of the low-dose combination was further confirmed in clonogenic assays and in mice xenografts. The presence of an ATM mutation predicted the activity of the combination in a model of patient-derived 3D spheroid.
Conclusions
This work demonstrates that the subset of CRCs carrying heterozygous ATM mutations may benefit from a combination treatment with low doses of niraparib and irinotecan. These data suggest a new potential approach in the treatment of ATM-mutated CRC, up to 10% in large datasets, that deserves to be validated prospectively in clinical trials.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Regione Campania - progetto I-CURE Università della Campania \"Luigi Vanvitelli\".
Disclosure
P.P. Vitiello: Advisory/Consultancy: Biocartis. T. Troiani: Advisory/Consultancy: Amgen; Advisory/Consultancy: Bayer; Advisory/Consultancy: Merck; Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche; Advisory/Consultancy: Sanofi. F. Ciardiello: Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy: Servier; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Symphogen; Research grant/Funding (institution): Ipsen. E. Martinelli: Advisory/Consultancy: Amgen; Advisory/Consultancy: Bayer; Advisory/Consultancy: Merck; Advisory/Consultancy: Roche; Advisory/Consultancy: Servier; Advisory/Consultancy: Sanofi. All other authors have declared no conflicts of interest.