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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

4688 - Combination treatment with the PARP inhibitor niraparib and chemotherapeutics in a preclinical model of KRAS/BRAF mutated colorectal cancer cell lines across the four Consensus Molecular Subtypes.

Date

21 Oct 2018

Session

Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

Presenters

Pietro Paolo Vitiello

Citation

Annals of Oncology (2018) 29 (suppl_8): viii1-viii13. 10.1093/annonc/mdy268

Authors

P.P. Vitiello, C. Cardone, D. Ciardiello, V. Belli, N. Matrone, C. Borrelli, L. Poliero, V. De Falco, E.F. Giunta, P. Vitale, N. Zanaletti, G. Tirino, T. Troiani, F. Ciardiello, E. Martinelli

Author affiliations

  • Medicina Di Precisione, Università degli Studi della Campania Luigi Vanvitelli, 80131 - Napoli/IT
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Resources

Abstract 4688

Background

DNA damage response (DDR) is crucial in a variety of tumours. Colorectal cancer (CRC) shows some features of dependency upon DDR such as frequent activation of RAS-MAPK pathway, that is strongly associated with mitotic stress. Moreover, several approved chemotherapeutics in CRC are typical DNA damaging agents that require active DDR systems in cancer cells to be tolerated (e.g. irinotecan and oxaliplatin). It has been recently shown that PARP inhibitors are able to potentiate the anti-proliferative effect of irinotecan and oxaliplatin, particularly in MSI tumours. However, there is still no correlation between niraparib response and Consensus Molecular Subtypes (CMS).

Methods

We analysed the sensitivity using MTT proliferation assay to the PARP-inhibitor niraparib used alone or in combination with either 5-fluorouracil (5FU), irinotecan (active metabolite SN38) or oxaliplatin in a panel of 8 KRAS (HCT15, LOVO, LS1034, SW1116, SW948, HCT116, SW480) or BRAF (WiDr) mutated CRCs, from the four CMS clusters. Combination index analysis was performed in order to evaluate the synergism between niraparib and the chemotherapeutics. Further characterization of sensitive cell lines was performed using western blot, cell cycle and apoptosis analyses.

Results

Niraparib showed synergistic activity when used in combination with chemotherapeutics in most cell lines used. In particular, the combination with SN38 exhibited the strongest synergism, while synergism with 5FU was only evident in a minority of the analysed cell lines. Synergistic effect between niraparib and chemotherapy was evidenced across all the four CMS. Cell cycle and apoptosis assays revealed differences in sensitive cell lines in terms of increased induction of apoptosis.

Conclusions

Combination of niraparib and chemotherapy in RAS/BRAF mutated CRC is synergistic irrespectively of CMS. SN38 is the best candidate for combination. Further analyses are needed in order to find other markers predictive of good response to PARP inhibitors and chemotherapy in this model.

Clinical trial identification

Legal entity responsible for the study

Department of Precision Medicine, Università della Campania Luigi Vanvitelli.

Funding

Has not received any funding.

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.

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