1. Disease Modeling on Tumor Organoids Implicates AURKA as a Therapeutic Target in Liver Metastatic Colorectal CancerSummary
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Leon P. Loevenich, Thomas Engleitner, Marlies Michl, Sebastian Vosberg, Matjaz Rokavec, Andreas Jung, Heiko Hermeking, Philipp A. Greif, Jens Neumann, Jörg Kumbrink, Roland Rad, Thomas Kirchner, Peter Jung, Rupert Öllinger, and Sophie L. Boos more...
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Colorectal cancer ,EdU, 5-ethynyl-2’-deoxyuridine ,RNP, ribonucleoprotein ,Cetuximab ,RC799-869 ,DMSO, dimethyl sulfoxide ,medicine.disease_cause ,MEK, mitogen-activated protein/extracellular signal-regulated kinase kinase ,eKRAS, clustered regularly interspaced short palindromic repeats/Cas9-generated KRASG12D ,PDTO, patient-derived tumor organoid ,PCR, polymerase chain reaction ,ERK, extracellular signal-regulated kinase ,GSEA, gene set enrichment analysis ,IC50, half-maximal inhibitory concentration ,CT-PDTO, chemotherapy-adapted patient-derived tumor organoid ,5’-FU, 5-fluorouracil ,Medicine ,E2F1 ,Epidermal growth factor receptor ,ANOVA, analysis of variance ,Original Research ,Aurora Kinase A ,biology ,TOC, tumor organoid culture ,Liver Neoplasms ,Gastroenterology ,AfaSel, afatinib + selumetinib ,FOLFIRI, folinic acid ,Combination chemotherapy ,Diseases of the digestive system. Gastroenterology ,ADF, advanced Dulbecco’s modified Eagle medium/F12 ,FFPE, formalin-fixed paraffin-embedded ,Organoids ,CRISPR, clustered regularly interspaced short palindromic repeats ,CRC, colorectal cancer ,FOLFIRI ,Cas9, CRISPR-associated 9 protein ,5’-FU, irinotecan (or SN-38) ,KRAS ,Colorectal Neoplasms ,SN-38, irinotecan active metabolite ,Chemoresistance ,medicine.drug ,AURKA, Aurora kinase A ,CRC Organoid ,c-MYC, c-MYC oncogene ,cDNA, complementary DNA ,Cmab, cetuximab ,E2F, E2 transcription factor ,RAS, rat sarcoma viral oncogene homolog ,3D, 3-dimensional ,Humans ,MSI, microsatellite instable ,UMI, unique molecular identifier ,EGF, epidermal growth factor ,HER, human epithelial growth factor receptor ,Hepatology ,business.industry ,PARP, poly-adenosine diphosphate ribose polymerase ,LMU, Ludwig-Maximilians-University ,medicine.disease ,digestive system diseases ,EGFR, epidermal growth factor receptor ,Cancer research ,biology.protein ,TCGA, The Cancer Genome Atlas ,business ,MAPK, mitogen-activated protein kinase - Abstract
Background & Aims Patient-derived tumor organoids recapitulate the characteristics of colorectal cancer (CRC) and provide an ideal platform for preclinical evaluation of personalized treatment options. We aimed to model the acquisition of chemotolerance during first-line combination chemotherapy in metastatic CRC organoids. Methods We performed next-generation sequencing to study the evolution of KRAS wild-type CRC organoids during adaptation to irinotecan-based chemotherapy combined with epidermal growth factor receptor (EGFR) inhibition. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 protein (Cas9)-editing showed the specific effect of KRASG12D acquisition in drug-tolerant organoids. Compound treatment strategies involving Aurora kinase A (AURKA) inhibition were assessed for their capability to induce apoptosis in a drug-persister background. Immunohistochemical detection of AURKA was performed on a patient-matched cohort of primary tumors and derived liver metastases. Results Adaptation to combination chemotherapy was accompanied by transcriptomic rather than gene mutational alterations in CRC organoids. Drug-tolerant cells evaded apoptosis and up-regulated MYC (c-myelocytomatosis oncogene product)/E2F1 (E2 family transcription factor 1) and/or interferon-α–related gene expression. Introduction of KRASG12D further increased the resilience of drug-persister CRC organoids against combination therapy. AURKA inhibition restored an apoptotic response in drug-tolerant KRAS–wild-type organoids. In dual epidermal growth factor receptor (EGFR)– pathway blockade-primed CRC organoids expressing KRASG12D, AURKA inhibition augmented apoptosis in cases that had acquired increased c-MYC protein levels during chemotolerance development. In patient-matched CRC cohorts, AURKA expression was increased in primary tumors and derived liver metastases. Conclusions Our study emphasizes the potential of patient-derived CRC organoids in modeling chemotherapy tolerance ex vivo. The applied therapeutic strategy of dual EGFR pathway blockade in combination with AURKA inhibition may prove effective for second-line treatment of chemotolerant CRC liver metastases with acquired KRAS mutation and increased AURKA/c-MYC expression., Graphical abstract more...
- Published
- 2022