PURPOSE: Defects in the homologous recombination (HR) repair pathway are of clinical interest due to sensitivity of HR-deficient cells to poly (ADP-ribose) polymerase (PARP) inhibitors. We were interested in defining PARP vulnerability in patients with metastatic colorectal cancer (mCRC) carrying KRAS and BRAF mutations that display poor prognosis, have limited therapeutic options and represent an unmet clinical need. EXPERIMENTAL DESIGN: We tested CRC cell lines, patient-derived organoids (PDOs) and patient-derived xenografts (PDXs) 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 CRC models were compared to pharmacological response. RESULTS: Thirteen out of ninety-nine (around 13%) CRC 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 CRC 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 CRC 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 CRC patients likely to benefit from olaparib. As mCRC patients almost invariably receive therapies based on oxaliplatin, 'maintenance' treatment with PARP inhibitors warrants further clinical investigation.

A subset of colorectal cancers with cross-sensitivity to olaparib and oxaliplatin / S. Arena, G. Corti, E. Durinikova, M. Montone, N.M. Reilly, M. Russo, A. Lorenzato, P. Arcella, L. Lazzari, G. Rospo, M. Pagani, C. Cancelliere, C. Negrino, C. Isella, A. Bartolini, A. Cassingena, A. Amatu, G. Mauri, A. Sartore-Bianchi, G. Mittica, E. Medico, S. Marsoni, M. Linnebacher, S. Abrignani, S. Siena, F. Di Nicolantonio, A. Bardelli. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - 26:5(2020), pp. 1372-1384.

A subset of colorectal cancers with cross-sensitivity to olaparib and oxaliplatin

M. Pagani;G. Mauri;A. Sartore-Bianchi;S. Abrignani;S. Siena;
2020

Abstract

PURPOSE: Defects in the homologous recombination (HR) repair pathway are of clinical interest due to sensitivity of HR-deficient cells to poly (ADP-ribose) polymerase (PARP) inhibitors. We were interested in defining PARP vulnerability in patients with metastatic colorectal cancer (mCRC) carrying KRAS and BRAF mutations that display poor prognosis, have limited therapeutic options and represent an unmet clinical need. EXPERIMENTAL DESIGN: We tested CRC cell lines, patient-derived organoids (PDOs) and patient-derived xenografts (PDXs) 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 CRC models were compared to pharmacological response. RESULTS: Thirteen out of ninety-nine (around 13%) CRC 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 CRC 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 CRC 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 CRC patients likely to benefit from olaparib. As mCRC patients almost invariably receive therapies based on oxaliplatin, 'maintenance' treatment with PARP inhibitors warrants further clinical investigation.
DNA-repair defects; cell-lines reveals; ovarian-cancer; double-blind; maintenance therapy; BRCA1/2 mutation; PARP inhibitors; breast-cancer; open-label; phase-I
Settore MED/06 - Oncologia Medica
2020
12-dic-2019
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/696811
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