A small molecule approach to degrade RAS with EGFR repression is a potential therapy for KRAS mutation-driven colorectal cancer resistance to cetuximab

Sang Kyu Lee; Yong Hee Cho; Pu Hyeon Cha; Jeong Soo Yoon; Eun Ji Ro; Woo Jeong Jeong; Jieun Park; Hyuntae Kim; Tae Il Kim; Do Sik Min; Gyoonhee Han; Kang Yell Choi

doi:10.1038/s12276-018-0182-2

A small molecule approach to degrade RAS with EGFR repression is a potential therapy for KRAS mutation-driven colorectal cancer resistance to cetuximab

Sang Kyu Lee, Yong Hee Cho, Pu Hyeon Cha, Jeong Soo Yoon, Eun Ji Ro, Woo Jeong Jeong, Jieun Park, Hyuntae Kim, Tae Il Kim, Do Sik Min, Gyoonhee Han, Kang Yell Choi

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Abstract

Drugs targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, have been prescribed for metastatic colorectal cancer (CRC), but patients harboring KRAS mutations are insensitive to them and do not have an alternative drug to overcome the problem. The levels of β-catenin, EGFR, and RAS, especially mutant KRAS, are increased in CRC patient tissues due to mutations of adenomatous polyposis coli (APC), which occur in 90% of human CRCs. The increases in these proteins by APC loss synergistically promote tumorigenesis. Therefore, we tested KYA1797K, a recently identified small molecule that degrades both β-catenin and Ras via GSK3β activation, and its capability to suppress the cetuximab resistance of KRAS-mutated CRC cells. KYA1797K suppressed the growth of tumor xenografts induced by CRC cells as well as tumor organoids derived from CRC patients having both APC and KRAS mutations. Lowering the levels of both β-catenin and RAS as well as EGFR via targeting the Wnt/β-catenin pathway is a therapeutic strategy for controlling CRC and other types of cancer with aberrantly activated the Wnt/β-catenin and EGFR-RAS pathways, including those with resistance to EGFR-targeting drugs attributed to KRAS mutations.

Original language	English
Article number	153
Journal	Experimental and Molecular Medicine
Volume	50
Issue number	11
DOIs	https://doi.org/10.1038/s12276-018-0182-2
Publication status	Published - 2018 Nov 1

Bibliographical note

Funding Information:
We thank Drs. B. Vogelstein and K.W. Kinzler for providing the DLD-1 isogenic cells. This study was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIP) (Grants 2016R1A5A1004694, 2015R1A2A1A05001873). Grant: This study was supported by National Research of Korea (NRF) grants funded by the Korean government (MSIP) (Grants: 2016R1A5A1004694, 2015R1A2A1A05001873) 1Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea. 2Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea. 3Department of Internal Medicine and Institute of Gastroenterology, College of Medicine, Yonsei University, Seoul, Korea. 4Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan, Korea

Publisher Copyright:
© 2018, The Author(s).

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Clinical Biochemistry

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s12276-018-0182-2

Cite this

Lee, S. K., Cho, Y. H., Cha, P. H., Yoon, J. S., Ro, E. J., Jeong, W. J., Park, J., Kim, H., Il Kim, T., Min, D. S., Han, G., & Choi, K. Y. (2018). A small molecule approach to degrade RAS with EGFR repression is a potential therapy for KRAS mutation-driven colorectal cancer resistance to cetuximab. Experimental and Molecular Medicine, 50(11), [153]. https://doi.org/10.1038/s12276-018-0182-2

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title = "A small molecule approach to degrade RAS with EGFR repression is a potential therapy for KRAS mutation-driven colorectal cancer resistance to cetuximab",

abstract = "Drugs targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, have been prescribed for metastatic colorectal cancer (CRC), but patients harboring KRAS mutations are insensitive to them and do not have an alternative drug to overcome the problem. The levels of β-catenin, EGFR, and RAS, especially mutant KRAS, are increased in CRC patient tissues due to mutations of adenomatous polyposis coli (APC), which occur in 90% of human CRCs. The increases in these proteins by APC loss synergistically promote tumorigenesis. Therefore, we tested KYA1797K, a recently identified small molecule that degrades both β-catenin and Ras via GSK3β activation, and its capability to suppress the cetuximab resistance of KRAS-mutated CRC cells. KYA1797K suppressed the growth of tumor xenografts induced by CRC cells as well as tumor organoids derived from CRC patients having both APC and KRAS mutations. Lowering the levels of both β-catenin and RAS as well as EGFR via targeting the Wnt/β-catenin pathway is a therapeutic strategy for controlling CRC and other types of cancer with aberrantly activated the Wnt/β-catenin and EGFR-RAS pathways, including those with resistance to EGFR-targeting drugs attributed to KRAS mutations.",

author = "Lee, {Sang Kyu} and Cho, {Yong Hee} and Cha, {Pu Hyeon} and Yoon, {Jeong Soo} and Ro, {Eun Ji} and Jeong, {Woo Jeong} and Jieun Park and Hyuntae Kim and {Il Kim}, Tae and Min, {Do Sik} and Gyoonhee Han and Choi, {Kang Yell}",

note = "Funding Information: We thank Drs. B. Vogelstein and K.W. Kinzler for providing the DLD-1 isogenic cells. This study was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIP) (Grants 2016R1A5A1004694, 2015R1A2A1A05001873). Grant: This study was supported by National Research of Korea (NRF) grants funded by the Korean government (MSIP) (Grants: 2016R1A5A1004694, 2015R1A2A1A05001873) 1Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea. 2Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea. 3Department of Internal Medicine and Institute of Gastroenterology, College of Medicine, Yonsei University, Seoul, Korea. 4Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan, Korea Publisher Copyright: {\textcopyright} 2018, The Author(s).",

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Lee, SK, Cho, YH, Cha, PH, Yoon, JS, Ro, EJ, Jeong, WJ, Park, J, Kim, H, Il Kim, T, Min, DS , Han, G & Choi, KY 2018, 'A small molecule approach to degrade RAS with EGFR repression is a potential therapy for KRAS mutation-driven colorectal cancer resistance to cetuximab', Experimental and Molecular Medicine, vol. 50, no. 11, 153. https://doi.org/10.1038/s12276-018-0182-2

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T1 - A small molecule approach to degrade RAS with EGFR repression is a potential therapy for KRAS mutation-driven colorectal cancer resistance to cetuximab

AU - Lee, Sang Kyu

AU - Cho, Yong Hee

AU - Cha, Pu Hyeon

AU - Yoon, Jeong Soo

AU - Ro, Eun Ji

AU - Jeong, Woo Jeong

AU - Park, Jieun

AU - Kim, Hyuntae

AU - Il Kim, Tae

AU - Min, Do Sik

AU - Han, Gyoonhee

AU - Choi, Kang Yell

N1 - Funding Information: We thank Drs. B. Vogelstein and K.W. Kinzler for providing the DLD-1 isogenic cells. This study was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIP) (Grants 2016R1A5A1004694, 2015R1A2A1A05001873). Grant: This study was supported by National Research of Korea (NRF) grants funded by the Korean government (MSIP) (Grants: 2016R1A5A1004694, 2015R1A2A1A05001873) 1Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea. 2Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea. 3Department of Internal Medicine and Institute of Gastroenterology, College of Medicine, Yonsei University, Seoul, Korea. 4Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan, Korea Publisher Copyright: © 2018, The Author(s).

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Drugs targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, have been prescribed for metastatic colorectal cancer (CRC), but patients harboring KRAS mutations are insensitive to them and do not have an alternative drug to overcome the problem. The levels of β-catenin, EGFR, and RAS, especially mutant KRAS, are increased in CRC patient tissues due to mutations of adenomatous polyposis coli (APC), which occur in 90% of human CRCs. The increases in these proteins by APC loss synergistically promote tumorigenesis. Therefore, we tested KYA1797K, a recently identified small molecule that degrades both β-catenin and Ras via GSK3β activation, and its capability to suppress the cetuximab resistance of KRAS-mutated CRC cells. KYA1797K suppressed the growth of tumor xenografts induced by CRC cells as well as tumor organoids derived from CRC patients having both APC and KRAS mutations. Lowering the levels of both β-catenin and RAS as well as EGFR via targeting the Wnt/β-catenin pathway is a therapeutic strategy for controlling CRC and other types of cancer with aberrantly activated the Wnt/β-catenin and EGFR-RAS pathways, including those with resistance to EGFR-targeting drugs attributed to KRAS mutations.

AB - Drugs targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, have been prescribed for metastatic colorectal cancer (CRC), but patients harboring KRAS mutations are insensitive to them and do not have an alternative drug to overcome the problem. The levels of β-catenin, EGFR, and RAS, especially mutant KRAS, are increased in CRC patient tissues due to mutations of adenomatous polyposis coli (APC), which occur in 90% of human CRCs. The increases in these proteins by APC loss synergistically promote tumorigenesis. Therefore, we tested KYA1797K, a recently identified small molecule that degrades both β-catenin and Ras via GSK3β activation, and its capability to suppress the cetuximab resistance of KRAS-mutated CRC cells. KYA1797K suppressed the growth of tumor xenografts induced by CRC cells as well as tumor organoids derived from CRC patients having both APC and KRAS mutations. Lowering the levels of both β-catenin and RAS as well as EGFR via targeting the Wnt/β-catenin pathway is a therapeutic strategy for controlling CRC and other types of cancer with aberrantly activated the Wnt/β-catenin and EGFR-RAS pathways, including those with resistance to EGFR-targeting drugs attributed to KRAS mutations.

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A small molecule approach to degrade RAS with EGFR repression is a potential therapy for KRAS mutation-driven colorectal cancer resistance to cetuximab

Abstract

Bibliographical note

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UN SDGs

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