A Subset of Colorectal Cancers with Cross-Sensitivity to Olaparib and Oxaliplatin
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 and mutations who display poor prognosis,...
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| Vydáno v: | Clinical cancer research Ročník 26; číslo 6; s. 1372 |
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| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
15.03.2020
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| ISSN: | 1557-3265, 1557-3265 |
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| Abstract | 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
and
mutations who display poor prognosis, have limited therapeutic options, and represent an unmet clinical need.
We tested colorectal cancer cell lines, patient-derived organoids (PDO), and patient-derived xenografts (PDX) enriched for
and
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.
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.
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. |
|---|---|
| AbstractList | 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
and
mutations who display poor prognosis, have limited therapeutic options, and represent an unmet clinical need.
We tested colorectal cancer cell lines, patient-derived organoids (PDO), and patient-derived xenografts (PDX) enriched for
and
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.
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.
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. 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.PURPOSEDefects 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.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.EXPERIMENTAL DESIGNWe 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.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.RESULTSThirteen 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.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.CONCLUSIONSThese 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. |
| Author | Mittica, Gloria Rospo, Giuseppe Cassingena, Andrea Abrignani, Sergio Arcella, Pamela Lazzari, Luca Di Nicolantonio, Federica Sartore-Bianchi, Andrea Medico, Enzo Linnebacher, Michael Russo, Mariangela Negrino, Carola Corti, Giorgio Arena, Sabrina Mauri, Gianluca Reilly, Nicole M Lorenzato, Annalisa Siena, Salvatore Pagani, Massimiliano Montone, Monica Marsoni, Silvia Bardelli, Alberto Durinikova, Erika Isella, Claudio Cancelliere, Carlotta Bartolini, Alice Amatu, Alessio |
| Author_xml | – sequence: 1 givenname: Sabrina orcidid: 0000-0002-1318-2494 surname: Arena fullname: Arena, Sabrina organization: Department of Oncology, University of Torino, Candiolo, Torino, Italy – sequence: 2 givenname: Giorgio orcidid: 0000-0001-6379-4117 surname: Corti fullname: Corti, Giorgio organization: Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy – sequence: 3 givenname: Erika surname: Durinikova fullname: Durinikova, Erika organization: Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy – sequence: 4 givenname: Monica orcidid: 0000-0001-7907-4333 surname: Montone fullname: Montone, Monica organization: Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy – sequence: 5 givenname: Nicole M orcidid: 0000-0002-8059-8422 surname: Reilly fullname: Reilly, Nicole M organization: Fondazione Piemontese per la Ricerca sul Cancro ONLUS, Candiolo, Torino, Italy – sequence: 6 givenname: Mariangela orcidid: 0000-0003-4625-1449 surname: Russo fullname: Russo, Mariangela organization: Department of Oncology, University of Torino, Candiolo, Torino, Italy – sequence: 7 givenname: Annalisa surname: Lorenzato fullname: Lorenzato, Annalisa organization: Department of Oncology, University of Torino, Candiolo, Torino, Italy – sequence: 8 givenname: Pamela surname: Arcella fullname: Arcella, Pamela organization: Department of Oncology, University of Torino, Candiolo, Torino, Italy – sequence: 9 givenname: Luca surname: Lazzari fullname: Lazzari, Luca organization: IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy – sequence: 10 givenname: Giuseppe orcidid: 0000-0002-1757-9085 surname: Rospo fullname: Rospo, Giuseppe organization: Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy – sequence: 11 givenname: Massimiliano orcidid: 0000-0002-7017-9304 surname: Pagani fullname: Pagani, Massimiliano organization: Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy – sequence: 12 givenname: Carlotta surname: Cancelliere fullname: Cancelliere, Carlotta organization: Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy – sequence: 13 givenname: Carola orcidid: 0000-0002-9422-7761 surname: Negrino fullname: Negrino, Carola organization: Department of Oncology, University of Torino, Candiolo, Torino, Italy – sequence: 14 givenname: Claudio orcidid: 0000-0003-0679-4756 surname: Isella fullname: Isella, Claudio organization: Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy – sequence: 15 givenname: Alice orcidid: 0000-0003-3492-0772 surname: Bartolini fullname: Bartolini, Alice organization: Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy – sequence: 16 givenname: Andrea surname: Cassingena fullname: Cassingena, Andrea organization: Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy – sequence: 17 givenname: Alessio surname: Amatu fullname: Amatu, Alessio organization: Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy – sequence: 18 givenname: Gianluca surname: Mauri fullname: Mauri, Gianluca organization: Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy – sequence: 19 givenname: Andrea orcidid: 0000-0003-0780-0409 surname: Sartore-Bianchi fullname: Sartore-Bianchi, Andrea organization: Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy – sequence: 20 givenname: Gloria surname: Mittica fullname: Mittica, Gloria organization: Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Torino, Italy – sequence: 21 givenname: Enzo surname: Medico fullname: Medico, Enzo organization: Department of Oncology, University of Torino, Candiolo, Torino, Italy – sequence: 22 givenname: Silvia surname: Marsoni fullname: Marsoni, Silvia organization: Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy – sequence: 23 givenname: Michael orcidid: 0000-0001-8054-1402 surname: Linnebacher fullname: Linnebacher, Michael organization: Department of General Surgery, Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany – sequence: 24 givenname: Sergio orcidid: 0000-0002-0794-3285 surname: Abrignani fullname: Abrignani, Sergio organization: Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy – sequence: 25 givenname: Salvatore orcidid: 0000-0002-2681-2846 surname: Siena fullname: Siena, Salvatore organization: Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy – sequence: 26 givenname: Federica orcidid: 0000-0001-9618-2010 surname: Di Nicolantonio fullname: Di Nicolantonio, Federica email: alberto.bardelli@unito.it, federica.dinicolantonio@unito.it organization: Department of Oncology, University of Torino, Candiolo, Torino, Italy – sequence: 27 givenname: Alberto surname: Bardelli fullname: Bardelli, Alberto email: alberto.bardelli@unito.it, federica.dinicolantonio@unito.it organization: Department of Oncology, University of Torino, Candiolo, Torino, Italy |
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| SubjectTerms | Animals Antineoplastic Agents - pharmacology Cell Line, Tumor Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Colorectal Neoplasms - 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 |
| Title | A Subset of Colorectal Cancers with Cross-Sensitivity to Olaparib and Oxaliplatin |
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