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KLF4 P.A472D Mutation Contributes to Acquired Resistance to Cetuximab In

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KLF4 P.A472D Mutation Contributes to Acquired Resistance to Cetuximab In Author Manuscript Published OnlineFirst on January 10, 2020; DOI: 10.1158/1535-7163.MCT-18-1385 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 KLF4 p.A472D Mutation Contributes to Acquired Resistance to Cetuximab in 2 Colorectal Cancer 3 Song Ye#,1, Xiaoge Hu#,2, Chao Ni#,2,3, Weiwei Jin4, Yaping Xu5, Lianpeng Chang5, Huaixiang 4 Zhou2, Jiahong Jiang*,2, Liu Yang*,2,4 5 1 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First 6 Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P. 7 R. China. 8 2 Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang 9 Province, Zhejiang Provincial People's Hospital, People’s Hospital of Hangzhou Medical 10 College, Hangzhou, Zhejiang 310014, P.R. China. 11 3 Department of General surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of 12 Hangzhou Medical College, Hangzhou, Zhejiang 310014, P. R. China. 13 4 Department of Gastroenterology & Pancreatic Surgery，Key Labatory of Gastroenterology， 14 Zhejiang Provincial People's Hospital, Hangzhou Medical College, Zhejiang 310014, P. R. 15 China. 16 5 Geneplus-Beijing Institute, Beijing 102206, P. R. China. 17 18 Running title: Acquired resistant mutation to cetuximab in CRC 19 Keywords: metastatic colorectal cancer, KLF4, acquired resistance, ctDNA, cetuximab 20 21 # These authors contributed equally to this work. 22 *Corresponding authors: 23 Liu Yang, Email: [email protected] 24 Jiahong Jiang, Email: [email protected] 25 Address: Zhejiang Provincial People's Hospital, Shang Tang Road 158, Hangzhou, Zhejiang 26 310014, P.R. China. 27 Conflicts of interest: The authors declare no potential conflicts of interest. 28 Word count: 4130 29 The total number of figures and tables: six figures and two tables. 30 1 Downloaded from mct.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 10, 2020; DOI: 10.1158/1535-7163.MCT-18-1385 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Financial Information：This work is supported by the Science Technology Department of 2 Zhejiang Province (No. 2016C33116), the CSCO Merck Serono Oncology Research Fund, 3 SCORE (No. Y-MX2015-038), the National Natural Science Fundation of China 4 (No.81772575), the key project of Health Bureau of Zhejiang Province (No. 2018274734), 5 and the Natural Science Fundation of Zhejiang Province (No. LY15H160053). 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 2 Downloaded from mct.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 10, 2020; DOI: 10.1158/1535-7163.MCT-18-1385 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Abstract 2 With the increase of treatment course, resistance to epidermal growth factor receptor (EGFR) 3 blockade is inevitable in patients with metastatic colorectal cancer (mCRC). KRAS mutations 4 have been considered to be primary drivers of this resistance; however, the potential function 5 of other genes has not been extensively investigated. This study collected 17 plasma samples 6 from mCRC patients with cetuximab resistance, and target-capture deep sequencing was used 7 to identify mutations in circulating tumor DNA (ctDNA). Analysis of mutational prevalence 8 in ctDNA was performed from three CRC tissue-based datasets and one ctDNA dataset. The 9 prevalence of mutations identified in ctDNA was consistent with both CRC tissue-based and 10 ctDNA datasets. Clonal analysis revealed that 41.2% of patients were positive for at least one 11 subclone. Multiple mechanisms of cetuximab resistance were co-existed in individual patients, 12 and one of the patients even harbored nine distinct mutations. In particular, functional study 13 of Krüppel-like factor 4 (KLF4) p.A472D revealed increased cetuximab resistance in CRC 14 cells, which was associated with the increased phosphorylation of downstream EGFR 15 signaling proteins. These results suggest that the KLF4 p.A472D may contribute to cetuximab 16 resistance in patients with mCRC and thus, it may serve as a new biomarker in clinical 17 application. Monitoring somatic mutations related to cetuximab resistance in mCRC patients 18 through ctDNA may provide real-time insights for clinical reference and treatment planning. 19 20 Introduction 21 Epidermal growth factor receptor (EGFR) plays an important role in tumor proliferation, 22 migration and invasion, and it is also one of the targets for molecular therapy in metastatic 23 colorectal cancer (mCRC) (1). Cetuximab, a human–mouse chimeric IgG1 monoclonal 24 antibody (mAb) targeting to the extracellular domain of EGFR, has been proven to be 25 effective in treating RAS wild-type and BRAF V600E wild-type mCRC patients (2, 3). 26 However, cetuximab resistance is generally inevitable in the course of disease progression, 27 even in patients who initially respond to EGFR mAbs (4). Various mechanisms have been 28 proposed to explain how this resistance develops, including mutations in the EGFR receptor 29 and its intracellular signal transduction intermediates, such as the mTOR/PI3K/AKT and 30 RAS/RAF/ERK/MEK pathways (5-8). HER-2 amplification and PTEN loss may also be 3 Downloaded from mct.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 10, 2020; DOI: 10.1158/1535-7163.MCT-18-1385 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 regarded as prognostic biomarkers for cetuximab resistance of KRAS wild-type patients (9, 2 10).We hypothesized that in addition to these previously documented mutations, there may be 3 other mutations contributing to the cetuximab resistance. 4 Recent studies have demonstrated that tumor-specific DNA mutations can be detected in 5 circulating tumor DNA (ctDNA) from peripheral blood by next generation sequencing (NGS), 6 allowing for the detection of novel mutations during cetuximab treatment (8, 11, 12). Analysis 7 of ctDNA is beneficial because it can not only identify specific somatic mutations of plasma 8 samples, but also provide a measurement suitable for non-invasive molecular characterization 9 of tumors. 10 In this study, we aim to explore novel biomarkers in ctDNA of mCRC patients exhibiting 11 cetuximab resistance for clinical use. 17 mCRC patients with cetuximab resistance were 12 enrolled to identify mutations in ctDNA. Then we compared the mutation prevalence from 13 our data with public datasets. We also evaluated the frequency and distribution of newly 14 detected somatic mutations associated with key components of EGFR signaling pathway. 15 Moreover, we revealed heterogeneity in the context of cetuximab resistance, and 16 demonstrated that specific mutation has the potential to serve as a biomarker for cetuximab 17 resistance through functional study. 18 19 Materials and Methods 20 Patient characteristics 21 Eligible patients were confirmed as mCRC and suitable for cetuximab therapy in this 22 study. Regardless of previous treatments, cetuximab could be used alone or in combination 23 with chemotherapy for patients in this study. The inclusion criteria were as follows: 1. 24 Patients with a pathologically confirmed diagnosis of mCRC; 2. Patients with wild-type RAS 25 (including KRAS and NRAS on exon 2, 3, 4) and wild-type BRAF sequences, confirmed by 26 sequencing; 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 27 (13); 4. Any previous treatment with the exception of cetuximab; 5. Provided written 28 informed consent. 29 Response evaluation was based on computed tomography scan (every 4-8 weeks), and 30 levels of tumor markers including cancer antigen 19-9 (CA 19-9) and serum 4 Downloaded from mct.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 10, 2020; DOI: 10.1158/1535-7163.MCT-18-1385 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 carcinoembryonic antigen (CEA) (every therapeutic cycle). Response Evaluation Criteria in 2 Solid Tumors (RECIST version 1.1) was used to assess treatment effectiveness and monitor 3 tumor progression (14). We defined primary resistance as progression-free survival (PFS) <12 4 weeks and acquired resistance as PFS ≥12weeks (15). The study was approved by the Ethics 5 Committees of Zhejiang Provincial People’s Hospital (2016KY123), and all participants 6 provided written informed consents. 7 Sample processing and DNA extraction 8 At least 10ml of peripheral blood from eligible patient was collected using Streck tubes 9 (Omaha, NE, USA). Within 72h after collection, these blood samples were separated by 10 centrifugation at 1,600 g for 10 min, and were then transferred to microcentrifuge tubes and 11 centrifuged at 16,000 g for 10 min to remove cellular debris. For isolated peripheral blood 12 lymphocytes (PBLs), genomic DNA was extracted using QIAamp DNA Blood Mini Kit 13 (Qiagen, Hilden, Germany). Circulating cell-free DNA was extracted from plasma using the 14 QIAamp Circulating Nucleic Acid Kit (Qiagen, Hilden, Germany), and was quantified using a 15 Qubit fluorometer and a Qubit dsDNA High Sensitivity Assay Kit (Invitrogen, Carlsbad, CA, 16 USA). The length of cell-free DNA fragments was measured with an Agilent 2100 17 Bioanalyzer and the DNA HS kit (Agilent Technologies, Santa Clara, UT, USA). 18 Library preparation, hybridization capture and sequencing 19 Genomic DNA was fragmented into 200-250bp segments using a Covaris S2 instrument 20 (Woburn, MA, USA). After an end repair and A-tailing reaction for cell-free DNA, adapters 21 with specific base sequence (unique identifiers, UIDs) were ligated to both ends of 22 double-stranded molecules, and fragment amplification was performed by PCR.
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