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EMT-mediated regulation of CXCL1/5 for resistance to anti-EGFR therapy in colorectal cancer

Oncogene volume 41, pages 2026–2038 (2022)Cite this article

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Abstract

The emergence of RAS/RAF mutant clone is the main feature of EGFR inhibitor resistance in KRAS wild-type colon cancer. However, its molecular mechanism is thought to be multifactorial, mainly due to cellular heterogeneity. In order to better understand the resistance mechanism in a single clone level, we successfully isolated nine cells with cetuximab-resistant (CR) clonality from in vitro system. All CR cells harbored either KRAS or BRAF mutations. Characteristically, these cells showed a higher EMT (Epithelial to mesenchymal transition) signature, showing increased EMT markers such as SNAI2. Moreover, the expression level of CXCL1/5, a secreted protein, was significantly higher in CR cells compared to the parental cells. In these CR cells, CXCL1/5 expression was coordinately regulated by SNAI2/NFKB and transactivated EGFR through CXCR/MMPI/EGF axis via autocrine singling. We also observed that combined cetuximab/MEK inhibitor not only showed growth inhibition but also reduced the secreted amounts of CXCL1/5. We further found that serum CXCL1/5 level was positively correlated with the presence of RAS/RAF mutation in colon cancer patients during cetuximab therapy, suggesting its role as a biomarker. These data indicated that the application of serum CXCL1/5 could be a potential serologic biomarker for predicting resistance to EGFR therapy in colorectal cancer.

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Fig. 1: Cetuximab-resistant cell lines have heterogeneity.
Fig. 2: Acquired resistance to cetuximab induces EMT through SNAI2 transcriptional regulation.
Fig. 3: CXCL1 and CXCL5 secreted from KRASMT/BRAFMT are regulated by RELA/SNAI2 as a co-effector.
Fig. 4: CXCL1 and CXCL5 induce resistance to cetuximab by transactivating EGFR via the CXCR2/MMP1/HB-EGF axis.
Fig. 5: Co-treatment with BRAF/MEK inhibitor decrease the secreted amounts of CXCL1/5 in CR cells.
Fig. 6: Secreted CXCL1 and CXCL5 can be detected in human blood samples.

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Acknowledgements

We thank H. Nikki March, Ph.D., from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. The authors are grateful to all members of our group for their helpful advice. This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare (HI14C1277, HI13C2096), by the Ministry of Science, ICT & Future Planning (2016M3A9B6026918, 2018R1C1B6005264), and by the National Research Foundation of Korea (2017M3C9A5029978), and by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT (NRF-2017M3A9A7050610).

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  1. These authors contributed equally: Ye-Lim Park, Hwang-Phill Kim.

Authors and Affiliations

  1. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea

    Ye-Lim Park, Hwang-Phill Kim, Jun Kyu Kang & Tae-You Kim

  2. Cancer Research Institute, Seoul National University, Seoul, Korea

    Ye-Lim Park, Hwang-Phill Kim, Dong-Wook Min, Jun Kyu Kang, Sang-Hyun Song, Sae-Won Han & Tae-You Kim

  3. IMBDx Inc, Seoul, Korea

    Hwang-Phill Kim

  4. Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

    Chan-Young Ock, Yoo Joo Lim, Sae-Won Han & Tae-You Kim

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Y-LP, H-PK, and T-YK conceived the project; Y-LP, D-WM established xenograft models Y-LP performed single-cell experiments; C-YO and JKK performed computational analysis; Y-LP designed and performed in vitro and in vivo experiments; Y-LP, H-PK, YJL, S-HS, S-WH, and T-YK interpreted data; Y-LP wrote the manuscript. All authors contributed edits and approved the final manuscript.

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Correspondence to Ye-Lim Park or Tae-You Kim.

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Park, YL., Kim, HP., Ock, CY. et al. EMT-mediated regulation of CXCL1/5 for resistance to anti-EGFR therapy in colorectal cancer. Oncogene 41, 2026–2038 (2022). https://doi.org/10.1038/s41388-021-01920-4

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