A Subset of Colorectal Cancers with Cross-Sensitivity to Olaparib and Oxaliplatin.

Abstract

PURPOSE:

Defects in the homologous recombination (HR) repair pathway are of clinical interest due to sensitivity of HR-deficient cells to PARP inhibitors. We were interested in defining PARP vulnerability in patients with metastatic colorectal cancer (mCRC) carrying KRAS and BRAF mutations who display poor prognosis, have limited therapeutic options, and represent an unmet clinical need.

EXPERIMENTAL DESIGN:

We tested colorectal cancer cell lines, patient-derived organoids (PDO), and patient-derived xenografts (PDX) enriched for KRAS and BRAF mutations for sensitivity to the PARP inhibitor olaparib, and the chemotherapeutic agents oxaliplatin and 5-fluorouracil (5-FU). Genomic profiles and DNA repair proficiency of colorectal cancer models were compared with pharmacologic response.

RESULTS:

Thirteen of 99 (around 13%) colorectal cancer cell lines were highly sensitive to clinically active concentrations of olaparib and displayed functional deficiency in HR. Response to PARP blockade was positively correlated with sensitivity to oxaliplatin in colorectal cancer cell lines as well as patient-derived organoids. Treatment of PDXs with olaparib impaired tumor growth and maintenance therapy with PARP blockade after initial oxaliplatin response delayed disease progression in mice.

CONCLUSIONS:

These results indicate that a colorectal cancer subset characterized by poor prognosis and limited therapeutic options is vulnerable to PARP inhibition and suggest that PDO-based drug-screening assays can be used to identify patients with colorectal cancer likely to benefit from olaparib. As patients with mCRC almost invariably receive therapies based on oxaliplatin, "maintenance" treatment with PARP inhibitors warrants further clinical investigation.

• Authors: Sabrina Arena, Giorgio Corti, Erika Durinikova, Monica Montone, Nicole M Reilly, Mariangela Russo, Annalisa Lorenzato, Pamela Arcella, Luca Lazzari, Giuseppe Rospo, Massimiliano Pagani, Carlotta Cancelliere, Carola Negrino, Claudio Isella, Alice Bartolini, Andrea Cassingena, Alessio Amatu, Gianluca Mauri, Andrea Sartore-Bianchi, Gloria Mittica, Enzo Medico, Silvia Marsoni, Michael Linnebacher, Sergio Abrignani, Salvatore Siena, Federica Di Nicolantonio, Alberto Bardelli
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 6 Pg. 1372-1384 (03 15 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 31831554 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• KRAS protein, human
• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• Oxaliplatin
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins p21(ras)
• olaparib

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, genetics, metabolism, pathology)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mutation
• Oxaliplatin (pharmacology)
• Phthalazines (pharmacology)
• Piperazines (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• Proto-Oncogene Proteins B-raf (genetics)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Recombinational DNA Repair
• Treatment Outcome
• Xenograft Model Antitumor Assays