Abstract The KRAS oncogene drives many common and highly fatal malignancies. These include pancreatic, lung, and colorectal cancer, where numerous different 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 overactive mutant forms to limit oncogenic KRAS signalling and maintain RAS- activity at an optimal level. Depletion of SHANK3 results in hyperactivation of KRAS/mitogen-activated protein kinase (MAPK) signalling, which in turn selectively induces MAPK/ERK-dependent cell death in KRAS -mutant cancers. Furthermore, targeting of this therapeutic vulnerability through nanobody- or RNA interference- mediated disruption of the SHANK3-KRAS interaction reduces tumour growth in vivo. Thus, inhibition of the SHANK3-KRAS interaction represents a new pan-KRAS-mutant compatible strategy for selective killing of KRAS - mutant cancer cells through excessive signalling. Graphical abstract Schematic model of SHANK3-controlled cell fate in KRAS -mutant cancers. SHANK3 directly interacts with KRAS and competes with RAF for KRAS binding to sustain oncogenic RAS-MAPK/ERK signalling at an optimal level (i.e. below toxic oncogenic signalling) in KRAS -mutant cancers. SHANK3 silencing (1) and inhibition of SHANK3-KRAS interaction (2) drive KRAS -mutant cells into cell death.

Targeting a broad spectrum of KRAS-mutant cancers by hyperactivation-induced cell death