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

©2019 American Association for Cancer Research..

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.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:26

Enthalten in:

Clinical cancer research : an official journal of the American Association for Cancer Research - 26(2020), 6 vom: 15. März, Seite 1372-1384

Sprache:

Englisch

Beteiligte Personen:

Arena, Sabrina [VerfasserIn]
Corti, Giorgio [VerfasserIn]
Durinikova, Erika [VerfasserIn]
Montone, Monica [VerfasserIn]
Reilly, Nicole M [VerfasserIn]
Russo, Mariangela [VerfasserIn]
Lorenzato, Annalisa [VerfasserIn]
Arcella, Pamela [VerfasserIn]
Lazzari, Luca [VerfasserIn]
Rospo, Giuseppe [VerfasserIn]
Pagani, Massimiliano [VerfasserIn]
Cancelliere, Carlotta [VerfasserIn]
Negrino, Carola [VerfasserIn]
Isella, Claudio [VerfasserIn]
Bartolini, Alice [VerfasserIn]
Cassingena, Andrea [VerfasserIn]
Amatu, Alessio [VerfasserIn]
Mauri, Gianluca [VerfasserIn]
Sartore-Bianchi, Andrea [VerfasserIn]
Mittica, Gloria [VerfasserIn]
Medico, Enzo [VerfasserIn]
Marsoni, Silvia [VerfasserIn]
Linnebacher, Michael [VerfasserIn]
Abrignani, Sergio [VerfasserIn]
Siena, Salvatore [VerfasserIn]
Di Nicolantonio, Federica [VerfasserIn]
Bardelli, Alberto [VerfasserIn]

Links:

Volltext

Themen:

04ZR38536J
Antineoplastic Agents
BRAF protein, human
EC 2.7.11.1
EC 3.6.5.2
Journal Article
KRAS protein, human
Olaparib
Oxaliplatin
Phthalazines
Piperazines
Poly(ADP-ribose) Polymerase Inhibitors
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins p21(ras)
Research Support, Non-U.S. Gov't
WOH1JD9AR8

Anmerkungen:

Date Completed 14.01.2021

Date Revised 14.01.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1158/1078-0432.CCR-19-2409

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM304327301