IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-52326-1.html
   My bibliography  Save this article

SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers

Author

Listed:
  • Johanna Lilja

    (University of Turku)

  • Jasmin Kaivola

    (University of Turku)

  • James R. W. Conway

    (University of Turku)

  • Joni Vuorio

    (University of Helsinki)

  • Hanna Parkkola

    (University of Turku)

  • Pekka Roivas

    (University of Turku
    University of Turku)

  • Michal Dibus

    (University of Turku)

  • Megan R. Chastney

    (University of Turku)

  • Taru Varila

    (University of Turku)

  • Guillaume Jacquemet

    (University of Turku
    Åbo Akademi University
    University of Turku and Åbo Akademi University
    Åbo Akademi University)

  • Emilia Peuhu

    (University of Turku
    University of Turku)

  • Emily Wang

    (University of Liverpool)

  • Ulla Pentikäinen

    (University of Turku
    University of Turku)

  • Itziar Martinez D. Posada

    (University of Turku)

  • Hellyeh Hamidi

    (University of Turku)

  • Arafath K. Najumudeen

    (University of Helsinki
    Garscube Estate)

  • Owen J. Sansom

    (Garscube Estate
    Garscube Estate)

  • Igor L. Barsukov

    (University of Liverpool)

  • Daniel Abankwa

    (University of Turku
    University of Luxembourg)

  • Ilpo Vattulainen

    (University of Helsinki)

  • Marko Salmi

    (University of Turku
    University of Turku
    University of Turku)

  • Johanna Ivaska

    (University of Turku
    University of Turku
    University of Turku
    Foundation for the Finnish Cancer Institute)

Abstract

The KRAS oncogene drives many common and highly fatal malignancies. These include pancreatic, lung, and colorectal cancer, where various activating KRAS mutations have made the development of KRAS inhibitors difficult. Here we identify the scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) as a RAS interactor that binds active KRAS, including mutant forms, competes with RAF and limits oncogenic KRAS downstream signalling, maintaining mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) activity at an optimal level. SHANK3 depletion breaches this threshold, triggering MAPK/ERK signalling hyperactivation and MAPK/ERK-dependent cell death in KRAS-mutant cancers. Targeting this vulnerability through RNA interference or nanobody-mediated disruption of the SHANK3–KRAS interaction constrains tumour growth in vivo in female mice. Thus, inhibition of SHANK3–KRAS interaction represents an alternative strategy for selective killing of KRAS-mutant cancer cells through excessive signalling.

Suggested Citation

  • Johanna Lilja & Jasmin Kaivola & James R. W. Conway & Joni Vuorio & Hanna Parkkola & Pekka Roivas & Michal Dibus & Megan R. Chastney & Taru Varila & Guillaume Jacquemet & Emilia Peuhu & Emily Wang & U, 2024. "SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52326-1
    DOI: 10.1038/s41467-024-52326-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-52326-1
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-52326-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Jude Canon & Karen Rex & Anne Y. Saiki & Christopher Mohr & Keegan Cooke & Dhanashri Bagal & Kevin Gaida & Tyler Holt & Charles G. Knutson & Neelima Koppada & Brian A. Lanman & Jonathan Werner & Aaron, 2019. "The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity," Nature, Nature, vol. 575(7781), pages 217-223, November.
    2. Jonathan M. Ostrem & Ulf Peters & Martin L. Sos & James A. Wells & Kevan M. Shokat, 2013. "K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions," Nature, Nature, vol. 503(7477), pages 548-551, November.
    3. Dongsung Kim & Lorenz Herdeis & Dorothea Rudolph & Yulei Zhao & Jark Böttcher & Alberto Vides & Carlos I. Ayala-Santos & Yasin Pourfarjam & Antonio Cuevas-Navarro & Jenny Y. Xue & Andreas Mantoulidis , 2023. "Pan-KRAS inhibitor disables oncogenic signalling and tumour growth," Nature, Nature, vol. 619(7968), pages 160-166, July.
    4. Yulei Zhao & Yonina R. Murciano-Goroff & Jenny Y. Xue & Agnes Ang & Jessica Lucas & Trang T. Mai & Arnaud F. Cruz Paula & Anne Y. Saiki & Deanna Mohn & Pragathi Achanta & Ann E. Sisk & Kanika S. Arora, 2021. "Diverse alterations associated with resistance to KRAS(G12C) inhibition," Nature, Nature, vol. 599(7886), pages 679-683, November.
    5. Joshua M. Dempster & Clare Pacini & Sasha Pantel & Fiona M. Behan & Thomas Green & John Krill-Burger & Charlotte M. Beaver & Scott T. Younger & Victor Zhivich & Hanna Najgebauer & Felicity Allen & Ema, 2019. "Agreement between two large pan-cancer CRISPR-Cas9 gene dependency data sets," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    6. Camilo Guzmán & Manish Bagga & Amanpreet Kaur & Jukka Westermarck & Daniel Abankwa, 2014. "ColonyArea: An ImageJ Plugin to Automatically Quantify Colony Formation in Clonogenic Assays," PLOS ONE, Public Library of Science, vol. 9(3), pages 1-9, March.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Marie-Julie Nokin & Alessia Mira & Enrico Patrucco & Biagio Ricciuti & Sophie Cousin & Isabelle Soubeyran & Sonia San José & Serena Peirone & Livia Caizzi & Sandra Vietti Michelina & Aurelien Bourdon , 2024. "RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Chi Zhou & Wenxin Li & Zhenxing Liang & Xianrui Wu & Sijing Cheng & Jianhong Peng & Kaixuan Zeng & Weihao Li & Ping Lan & Xin Yang & Li Xiong & Ziwei Zeng & Xiaobin Zheng & Liang Huang & Wenhua Fan & , 2024. "Mutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    3. Hidenori Kitai & Philip H. Choi & Yu C. Yang & Jacob A. Boyer & Adele Whaley & Priya Pancholi & Claire Thant & Jason Reiter & Kevin Chen & Vladimir Markov & Hirokazu Taniguchi & Rui Yamaguchi & Hiromi, 2024. "Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Kai-Bo Wang & Yushuang Liu & Jinzhu Li & Chengmei Xiao & Yingying Wang & Wei Gu & Yipu Li & Yuan-Zheng Xia & Tingdong Yan & Ming-Hua Yang & Ling-Yi Kong, 2022. "Structural insight into the bulge-containing KRAS oncogene promoter G-quadruplex bound to berberine and coptisine," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    5. Katharine M. Wright & Sarah R. DiNapoli & Michelle S. Miller & P. Aitana Azurmendi & Xiaowei Zhao & Zhiheng Yu & Mayukh Chakrabarti & WuXian Shi & Jacqueline Douglass & Michael S. Hwang & Emily Han-Ch, 2023. "Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    6. Irati Macaya & Marta Roman & Connor Welch & Rodrigo Entrialgo-Cadierno & Marina Salmon & Alba Santos & Iker Feliu & Joanna Kovalski & Ines Lopez & Maria Rodriguez-Remirez & Sara Palomino-Echeverria & , 2023. "Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    7. Sean A. Misek & Aaron Fultineer & Jeremie Kalfon & Javad Noorbakhsh & Isabella Boyle & Priyanka Roy & Joshua Dempster & Lia Petronio & Katherine Huang & Alham Saadat & Thomas Green & Adam Brown & John, 2024. "Germline variation contributes to false negatives in CRISPR-based experiments with varying burden across ancestries," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    8. Ci Fu & Xiang Zhang & Amanda O. Veri & Kali R. Iyer & Emma Lash & Alice Xue & Huijuan Yan & Nicole M. Revie & Cassandra Wong & Zhen-Yuan Lin & Elizabeth J. Polvi & Sean D. Liston & Benjamin VanderSlui, 2021. "Leveraging machine learning essentiality predictions and chemogenomic interactions to identify antifungal targets," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    9. Anthony V Furano & Charlie E Jones & Vipul Periwal & Kathryn E Callahan & Jean-Claude Walser & Pamela R Cook, 2020. "Cryptic genetic variation enhances primate L1 retrotransposon survival by enlarging the functional coiled coil sequence space of ORF1p," PLOS Genetics, Public Library of Science, vol. 16(8), pages 1-19, August.
    10. Dan Lu & Yuan Chen & Min Jiang & Jie Wang & Yiting Li & Keke Ma & Wenqiao Sun & Xing Zheng & Jianxun Qi & Wenjing Jin & Yu Chen & Yan Chai & Catherine W. H. Zhang & Hao Liang & Shuguang Tan & George F, 2023. "KRAS G12V neoantigen specific T cell receptor for adoptive T cell therapy against tumors," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    11. James Schiemer & Andrew Maxwell & Reto Horst & Shenping Liu & Daniel P. Uccello & Kris Borzilleri & Nisha Rajamohan & Matthew F. Brown & Matthew F. Calabrese, 2023. "A covalent BTK ternary complex compatible with targeted protein degradation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    12. Natalia Baran & Alessia Lodi & Yogesh Dhungana & Shelley Herbrich & Meghan Collins & Shannon Sweeney & Renu Pandey & Anna Skwarska & Shraddha Patel & Mathieu Tremblay & Vinitha Mary Kuruvilla & Antoni, 2022. "Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    13. Arafath K. Najumudeen & Sigrid K. Fey & Laura M. Millett & Catriona A. Ford & Kathryn Gilroy & Nuray Gunduz & Rachel A. Ridgway & Eve Anderson & Douglas Strathdee & William Clark & Colin Nixon & Jenni, 2024. "KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    14. Shizhong Ke & Fabin Dang & Lin Wang & Jia-Yun Chen & Mandar T. Naik & Wenxue Li & Abhishek Thavamani & Nami Kim & Nandita M. Naik & Huaxiu Sui & Wei Tang & Chenxi Qiu & Kazuhiro Koikawa & Felipe Batal, 2024. "Reciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    15. Caterina Bartolacci & Cristina Andreani & Gonçalo Vale & Stefano Berto & Margherita Melegari & Anna Colleen Crouch & Dodge L. Baluya & George Kemble & Kurt Hodges & Jacqueline Starrett & Katerina Poli, 2022. "Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    16. Ruitong Li & Olaf Klingbeil & Davide Monducci & Michael J. Young & Diego J. Rodriguez & Zaid Bayyat & Joshua M. Dempster & Devishi Kesar & Xiaoping Yang & Mahdi Zamanighomi & Christopher R. Vakoc & Ta, 2022. "Comparative optimization of combinatorial CRISPR screens," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    17. Haochen Zhang & Elias-Ramzey Karnoub & Shigeaki Umeda & Ronan Chaligné & Ignas Masilionis & Caitlin A. McIntyre & Palash Sashittal & Akimasa Hayashi & Amanda Zucker & Katelyn Mullen & Jungeui Hong & A, 2023. "Application of high-throughput single-nucleus DNA sequencing in pancreatic cancer," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    18. Nishanth Ulhas Nair & Patricia Greninger & Xiaohu Zhang & Adam A. Friedman & Arnaud Amzallag & Eliane Cortez & Avinash Das Sahu & Joo Sang Lee & Anahita Dastur & Regina K. Egan & Ellen Murchie & Miche, 2023. "A landscape of response to drug combinations in non-small cell lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    19. Peter Eirew & Ciara O’Flanagan & Jerome Ting & Sohrab Salehi & Jazmine Brimhall & Beixi Wang & Justina Biele & Teresa Algara & So Ra Lee & Corey Hoang & Damian Yap & Steven McKinney & Cherie Bates & E, 2022. "Accurate determination of CRISPR-mediated gene fitness in transplantable tumours," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    20. Gisele Nishiguchi & Lauren G. Mascibroda & Sarah M. Young & Elizabeth A. Caine & Sherif Abdelhamed & Jeffrey J. Kooijman & Darcie J. Miller & Sourav Das & Kevin McGowan & Anand Mayasundari & Zhe Shi &, 2024. "Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52326-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.