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; Johanna Ivaska

doi:10.1038/s41467-024-52326-1

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 VattulainenMarko Salmi, Johanna Ivaska

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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.

Original language	English
Article number	8002
Journal	Nature Communications
Volume	15
DOIs	https://doi.org/10.1038/s41467-024-52326-1
Publication status	Published - 12 Sept 2024
MoE publication type	A1 Journal article-refereed

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10.1038/s41467-024-52326-1Licence: CC BY-NC-ND

s41467-024-52326-1Final published version, 4.12 MBLicence: CC BY-NC-ND

https://urn.fi/URN:NBN:fi-fe20241216102789

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Lilja, J., Kaivola, J., Conway, J. R. W., Vuorio, J., Parkkola, H., Roivas, P., Dibus, M., Chastney, M. R., Varila, T., Jacquemet, G., Peuhu, E., Wang, E., Pentikäinen, U., Posada, I. M. D., Hamidi, H., Najumudeen, A. K., Sansom, O. J., Barsukov, I. L., Abankwa, D., ... Ivaska, J. (2024). SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers. Nature Communications, 15, Article 8002. https://doi.org/10.1038/s41467-024-52326-1

@article{2797e88f9e504d11a378afb7c6c1b335,

title = "SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers",

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.",

author = "Johanna Lilja and Jasmin Kaivola and Conway, {James R. W.} and Joni Vuorio and Hanna Parkkola and Pekka Roivas and Michal Dibus and Chastney, {Megan R.} and Taru Varila and Guillaume Jacquemet and Emilia Peuhu and Emily Wang and Ulla Pentik{\"a}inen and Posada, {Itziar Martinez D.} and Hellyeh Hamidi and Najumudeen, {Arafath K.} and Sansom, {Owen J.} and Barsukov, {Igor L.} and Daniel Abankwa and Ilpo Vattulainen and Marko Salmi and Johanna Ivaska",

year = "2024",

month = sep,

day = "12",

doi = "10.1038/s41467-024-52326-1",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

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Lilja, J, Kaivola, J, Conway, JRW, Vuorio, J, Parkkola, H, Roivas, P, Dibus, M, Chastney, MR, Varila, T, Jacquemet, G, Peuhu, E, Wang, E, Pentikäinen, U, Posada, IMD, Hamidi, H, Najumudeen, AK, Sansom, OJ, Barsukov, IL, Abankwa, D, Vattulainen, I, Salmi, M & Ivaska, J 2024, 'SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers', Nature Communications, vol. 15, 8002. https://doi.org/10.1038/s41467-024-52326-1

TY - JOUR

T1 - SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers

AU - Lilja, Johanna

AU - Kaivola, Jasmin

AU - Conway, James R. W.

AU - Vuorio, Joni

AU - Parkkola, Hanna

AU - Roivas, Pekka

AU - Dibus, Michal

AU - Chastney, Megan R.

AU - Varila, Taru

AU - Jacquemet, Guillaume

AU - Peuhu, Emilia

AU - Wang, Emily

AU - Pentikäinen, Ulla

AU - Posada, Itziar Martinez D.

AU - Hamidi, Hellyeh

AU - Najumudeen, Arafath K.

AU - Sansom, Owen J.

AU - Barsukov, Igor L.

AU - Abankwa, Daniel

AU - Vattulainen, Ilpo

AU - Salmi, Marko

AU - Ivaska, Johanna

PY - 2024/9/12

Y1 - 2024/9/12

N2 - 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.

AB - 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.

UR - https://doi.org/10.1038/s41467-024-52326-1

U2 - 10.1038/s41467-024-52326-1

DO - 10.1038/s41467-024-52326-1

M3 - Article

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

M1 - 8002

ER -

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

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