Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy

Yu Kai Huang; Wei Chung Cheng; Ting Ting Kuo; Juan Cheng Yang; Yang Chang Wu; Heng Hsiung Wu; Chia Chien Lo; Chih Ying Hsieh; Sze Ching Wong; Chih Hao Lu; Wan Ling Wu; Shih Jen Liu; Yi Chuan Li; Ching Chan Lin; Chia Ning Shen; Mien Chie Hung; Jaw Town Lin; Chun Chieh Yeh; Yuh Pyng Sher

doi:10.1038/s43018-023-00720-x

Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy

Yu Kai Huang, Wei Chung Cheng, Ting Ting Kuo, Juan Cheng Yang, Yang Chang Wu, Heng Hsiung Wu, Chia Chien Lo, Chih Ying Hsieh, Sze Ching Wong, Chih Hao Lu, Wan Ling Wu, Shih Jen Liu, Yi Chuan Li, Ching Chan Lin, Chia Ning Shen, Mien Chie Hung, Jaw Town Lin, Chun Chieh Yeh^*, Yuh Pyng Sher^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.

Original language	English
Pages (from-to)	400-419
Number of pages	20
Journal	Nature Cancer
Volume	5
Issue number	3
DOIs	https://doi.org/10.1038/s43018-023-00720-x
State	Published - Mar 2024

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Huang, Y. K., Cheng, W. C., Kuo, T. T., Yang, J. C., Wu, Y. C., Wu, H. H., Lo, C. C., Hsieh, C. Y., Wong, S. C., Lu, C. H., Wu, W. L., Liu, S. J., Li, Y. C., Lin, C. C., Shen, C. N., Hung, M. C., Lin, J. T., Yeh, C. C., & Sher, Y. P. (2024). Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy. Nature Cancer, 5(3), 400-419. https://doi.org/10.1038/s43018-023-00720-x

@article{a969ead190ed43c49dc566db6451dd0a,

title = "Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy",

abstract = "Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.",

author = "Huang, {Yu Kai} and Cheng, {Wei Chung} and Kuo, {Ting Ting} and Yang, {Juan Cheng} and Wu, {Yang Chang} and Wu, {Heng Hsiung} and Lo, {Chia Chien} and Hsieh, {Chih Ying} and Wong, {Sze Ching} and Lu, {Chih Hao} and Wu, {Wan Ling} and Liu, {Shih Jen} and Li, {Yi Chuan} and Lin, {Ching Chan} and Shen, {Chia Ning} and Hung, {Mien Chie} and Lin, {Jaw Town} and Yeh, {Chun Chieh} and Sher, {Yuh Pyng}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.",

year = "2024",

month = mar,

doi = "10.1038/s43018-023-00720-x",

language = "English",

volume = "5",

pages = "400--419",

journal = "Nature Cancer",

issn = "2662-1347",

publisher = "Nature Research",

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Huang, YK, Cheng, WC, Kuo, TT, Yang, JC, Wu, YC, Wu, HH, Lo, CC, Hsieh, CY, Wong, SC, Lu, CH, Wu, WL, Liu, SJ, Li, YC, Lin, CC, Shen, CN, Hung, MC, Lin, JT, Yeh, CC & Sher, YP 2024, 'Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy', Nature Cancer, vol. 5, no. 3, pp. 400-419. https://doi.org/10.1038/s43018-023-00720-x

TY - JOUR

T1 - Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy

AU - Huang, Yu Kai

AU - Cheng, Wei Chung

AU - Kuo, Ting Ting

AU - Yang, Juan Cheng

AU - Wu, Yang Chang

AU - Wu, Heng Hsiung

AU - Lo, Chia Chien

AU - Hsieh, Chih Ying

AU - Wong, Sze Ching

AU - Lu, Chih Hao

AU - Wu, Wan Ling

AU - Liu, Shih Jen

AU - Li, Yi Chuan

AU - Lin, Ching Chan

AU - Shen, Chia Ning

AU - Hung, Mien Chie

AU - Lin, Jaw Town

AU - Yeh, Chun Chieh

AU - Sher, Yuh Pyng

PY - 2024/3

Y1 - 2024/3

N2 - Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.

AB - Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.

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DO - 10.1038/s43018-023-00720-x

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AN - SCOPUS:85183028374

SN - 2662-1347

VL - 5

SP - 400

EP - 419

JO - Nature Cancer

JF - Nature Cancer

IS - 3

ER -

Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy

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