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

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, Ulla Pentikäinen, Itziar Martinez D. Posada, Hellyeh Hamidi, Arafath K. Najumudeen, Owen J. Sansom, Igor L. Barsukov, Daniel Abankwa, Ilpo Vattulainen, Marko Salmi and Johanna Ivaska ()
Additional contact information
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
Michal Dibus: University of Turku
Megan R. Chastney: University of Turku
Taru Varila: University of Turku
Guillaume Jacquemet: University of Turku
Emilia Peuhu: University of Turku
Emily Wang: University of Liverpool
Ulla Pentikäinen: University of Turku
Itziar Martinez D. Posada: University of Turku
Hellyeh Hamidi: University of Turku
Arafath K. Najumudeen: University of Helsinki
Owen J. Sansom: Garscube Estate
Igor L. Barsukov: University of Liverpool
Daniel Abankwa: University of Turku
Ilpo Vattulainen: University of Helsinki
Marko Salmi: University of Turku
Johanna Ivaska: University of Turku

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52326-1

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