Mismatch Repair Status in Patient-Derived Colorectal Cancer Organoids Does Not Affect Intrinsic Tumor Cell Sensitivity to Systemic Therapy

DNA mismatch repair deficiency (dMMR) in metastatic colorectal cancer (mCRC) is associated with poor survival and a poor response to systemic treatment. However, it is unclear whether dMMR results in a tumor cell-intrinsic state of treatment resistance, or whether alternative mechanisms play a role....

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Emre Küçükköse, G. Emerens Wensink, Celine M. Roelse, Susanne J. van Schelven, Daniëlle A. E. Raats, Sylvia F. Boj, Miriam Koopman, Jamila Laoukili, Jeanine M. L. Roodhart, Onno Kranenburg
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	organoids colorectal cancer deficient mismatch repair mutation drug screens Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/ca07995fd6bc49efbcb5b35f81d317dd
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ca07995fd6bc49efbcb5b35f81d317dd
record_format	dspace
spelling	oai:doaj.org-article:ca07995fd6bc49efbcb5b35f81d317dd2021-11-11T15:31:31ZMismatch Repair Status in Patient-Derived Colorectal Cancer Organoids Does Not Affect Intrinsic Tumor Cell Sensitivity to Systemic Therapy10.3390/cancers132154342072-6694https://doaj.org/article/ca07995fd6bc49efbcb5b35f81d317dd2021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5434https://doaj.org/toc/2072-6694DNA mismatch repair deficiency (dMMR) in metastatic colorectal cancer (mCRC) is associated with poor survival and a poor response to systemic treatment. However, it is unclear whether dMMR results in a tumor cell-intrinsic state of treatment resistance, or whether alternative mechanisms play a role. To address this, we generated a cohort of MMR-proficient and -deficient Patient-Derived Organoids (PDOs) and tested their response to commonly used drugs in the treatment of mCRC, including 5-fluorouracil (5-FU), oxaliplatin, SN-38, binimetinib, encorafenib, and cetuximab. MMR status did not correlate with the response of PDOs to any of the drugs tested. In contrast, the presence of activating mutations in the <i>KRAS</i> and <i>BRAF</i> oncogenes was significantly associated with resistance to chemotherapy and sensitivity to drugs targeting oncogene-activated pathways. We conclude that mutant KRAS and BRAF impact the intrinsic sensitivity of tumor cells to chemotherapy and targeted therapy. By contrast, tumor cell-extrinsic mechanisms—for instance signals derived from the microenvironment—must underlie the association of MMR status with therapy response. Future drug screens on rationally chosen cohorts of PDOs have great potential in developing tailored therapies for specific CRC subtypes including, but not restricted to, those defined by BRAF/KRAS and MMR status.Emre KüçükköseG. Emerens WensinkCeline M. RoelseSusanne J. van SchelvenDaniëlle A. E. RaatsSylvia F. BojMiriam KoopmanJamila LaoukiliJeanine M. L. RoodhartOnno KranenburgMDPI AGarticleorganoidscolorectal cancerdeficient mismatch repairmutationdrug screensNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5434, p 5434 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	organoids colorectal cancer deficient mismatch repair mutation drug screens Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	organoids colorectal cancer deficient mismatch repair mutation drug screens Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Emre Küçükköse G. Emerens Wensink Celine M. Roelse Susanne J. van Schelven Daniëlle A. E. Raats Sylvia F. Boj Miriam Koopman Jamila Laoukili Jeanine M. L. Roodhart Onno Kranenburg Mismatch Repair Status in Patient-Derived Colorectal Cancer Organoids Does Not Affect Intrinsic Tumor Cell Sensitivity to Systemic Therapy
description	DNA mismatch repair deficiency (dMMR) in metastatic colorectal cancer (mCRC) is associated with poor survival and a poor response to systemic treatment. However, it is unclear whether dMMR results in a tumor cell-intrinsic state of treatment resistance, or whether alternative mechanisms play a role. To address this, we generated a cohort of MMR-proficient and -deficient Patient-Derived Organoids (PDOs) and tested their response to commonly used drugs in the treatment of mCRC, including 5-fluorouracil (5-FU), oxaliplatin, SN-38, binimetinib, encorafenib, and cetuximab. MMR status did not correlate with the response of PDOs to any of the drugs tested. In contrast, the presence of activating mutations in the <i>KRAS</i> and <i>BRAF</i> oncogenes was significantly associated with resistance to chemotherapy and sensitivity to drugs targeting oncogene-activated pathways. We conclude that mutant KRAS and BRAF impact the intrinsic sensitivity of tumor cells to chemotherapy and targeted therapy. By contrast, tumor cell-extrinsic mechanisms—for instance signals derived from the microenvironment—must underlie the association of MMR status with therapy response. Future drug screens on rationally chosen cohorts of PDOs have great potential in developing tailored therapies for specific CRC subtypes including, but not restricted to, those defined by BRAF/KRAS and MMR status.
format	article
author	Emre Küçükköse G. Emerens Wensink Celine M. Roelse Susanne J. van Schelven Daniëlle A. E. Raats Sylvia F. Boj Miriam Koopman Jamila Laoukili Jeanine M. L. Roodhart Onno Kranenburg
author_facet	Emre Küçükköse G. Emerens Wensink Celine M. Roelse Susanne J. van Schelven Daniëlle A. E. Raats Sylvia F. Boj Miriam Koopman Jamila Laoukili Jeanine M. L. Roodhart Onno Kranenburg
author_sort	Emre Küçükköse
title	Mismatch Repair Status in Patient-Derived Colorectal Cancer Organoids Does Not Affect Intrinsic Tumor Cell Sensitivity to Systemic Therapy
title_short	Mismatch Repair Status in Patient-Derived Colorectal Cancer Organoids Does Not Affect Intrinsic Tumor Cell Sensitivity to Systemic Therapy
title_full	Mismatch Repair Status in Patient-Derived Colorectal Cancer Organoids Does Not Affect Intrinsic Tumor Cell Sensitivity to Systemic Therapy
title_fullStr	Mismatch Repair Status in Patient-Derived Colorectal Cancer Organoids Does Not Affect Intrinsic Tumor Cell Sensitivity to Systemic Therapy
title_full_unstemmed	Mismatch Repair Status in Patient-Derived Colorectal Cancer Organoids Does Not Affect Intrinsic Tumor Cell Sensitivity to Systemic Therapy
title_sort	mismatch repair status in patient-derived colorectal cancer organoids does not affect intrinsic tumor cell sensitivity to systemic therapy
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ca07995fd6bc49efbcb5b35f81d317dd
work_keys_str_mv	AT emrekucukkose mismatchrepairstatusinpatientderivedcolorectalcancerorganoidsdoesnotaffectintrinsictumorcellsensitivitytosystemictherapy AT gemerenswensink mismatchrepairstatusinpatientderivedcolorectalcancerorganoidsdoesnotaffectintrinsictumorcellsensitivitytosystemictherapy AT celinemroelse mismatchrepairstatusinpatientderivedcolorectalcancerorganoidsdoesnotaffectintrinsictumorcellsensitivitytosystemictherapy AT susannejvanschelven mismatchrepairstatusinpatientderivedcolorectalcancerorganoidsdoesnotaffectintrinsictumorcellsensitivitytosystemictherapy AT danielleaeraats mismatchrepairstatusinpatientderivedcolorectalcancerorganoidsdoesnotaffectintrinsictumorcellsensitivitytosystemictherapy AT sylviafboj mismatchrepairstatusinpatientderivedcolorectalcancerorganoidsdoesnotaffectintrinsictumorcellsensitivitytosystemictherapy AT miriamkoopman mismatchrepairstatusinpatientderivedcolorectalcancerorganoidsdoesnotaffectintrinsictumorcellsensitivitytosystemictherapy AT jamilalaoukili mismatchrepairstatusinpatientderivedcolorectalcancerorganoidsdoesnotaffectintrinsictumorcellsensitivitytosystemictherapy AT jeaninemlroodhart mismatchrepairstatusinpatientderivedcolorectalcancerorganoidsdoesnotaffectintrinsictumorcellsensitivitytosystemictherapy AT onnokranenburg mismatchrepairstatusinpatientderivedcolorectalcancerorganoidsdoesnotaffectintrinsictumorcellsensitivitytosystemictherapy
_version_	1718435269297831936

Mismatch Repair Status in Patient-Derived Colorectal Cancer Organoids Does Not Affect Intrinsic Tumor Cell Sensitivity to Systemic Therapy

Ejemplares similares