Pentikäinen, U. | bioRxiv Science

bioRxiv2025

Modulation of CIP2A dimerization and protein stability via druggable pocket

Cancerous inhibitor of PP2A (CIP2A) supports malignant growth across several cancer types. CIP2A is also a synthetic lethal therapy target for BRCA-mutant cancers. In addition, CIP2A causes Alzheime[r]s disease (AD) phenotype in mice. However, it is not dispensable for normal development and growth. Therefore, CIP2A is very lucrative therapy target in cancer and AD. So far it has been unclear whether the CIP2A protein harbors any druggable pockets amenable to targeting by small molecules. Here we discover a druggable pocket adjacent to the homodimerization domain of CIP2A. Mutagenesis demonstrates that pocket impacts CIP2A homodimerization, PP2A interaction, and full-length CIP2A protein stability in cancer cells. Further, we identify Gambogenic acid (GNA) as a tool compound that directly binds to CIP2A pocket region. GNA and its derivative Gambogic acid dissociate CIP2A homodimer in vitro and cause CIP2A destabilization in cellulo. The pocket contributes to the impact of GNA on homodimerization based on the protein fragment and mutagenesis analysis. These results identify structural vulnerability on CIP2A and may facilitate development of targeted CIP2A inhibitors with broad disease applicability.

biochemistry↗

bioRxiv2022

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

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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/508660v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@87e71forg.highwire.dtl.DTLVardef@56cf94org.highwire.dtl.DTLVardef@1561136org.highwire.dtl.DTLVardef@183f711_HPS_FORMAT_FIGEXP M_FIG C_FIG 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.

cancer biology↗