HotSpot Therapeutics presents preclinical data from the CARD11-BCL10-MALT1 (CBM) signalosome program
The development of these potent inhibitors of the CBM signalosome complex, shows promising results by demonstrating apoptosis and tumor growth inhibition
9 Jul 2025HotSpot Therapeutics presented preclinical data from the CARD11-BCL10-MALT1 (CBM) signalosome program at the European Society for Medical Oncology (ESMO) Gastrointestinal Cancers Congress 2025.
The CBM signalosome is a molecular hub that serves as a key regulator of multiple oncogenic pathways, including NFkB, JNK, mTORC1 and MYC. As such, the CBM signalosome serves as a critical regulator of tumor development and survival, particularly in KRAS-driven colorectal cancer (CRC), as well as other KRAS-driven cancers, including pancreatic and lung cancer.
Leveraging the company's proprietary Smart Allostery™ platform, HotSpot has discovered small molecule CBM signalosome inhibitors that bind and inactivate the complex, with preclinical data demonstrating dose-dependent tumor inhibition and regression in multiple KRAS-driven tumor models.
The poster presentations shared that:
- HotSpot's CBM signalosome inhibitors demonstrated selectively induced potent apoptosis in KRASG12 CRC cell lines, outperforming KRAS, BCL2 and Bcl-xL inhibitors.
- In combination with a KRAS inhibitor, HotSpot's CBM signalosome inhibitor achieved complete suppression of downstream signaling in KRASG12X cell lines.
- HotSpot's CBM signalosome inhibitor demonstrated dose-dependent tumor inhibition or regression both alone and in combination with a KRAS inhibitor in multiple in vivo models.
Geraldine Harriman, Ph.D., Chief Scientific Officer of HotSpot Therapeutics, said, "While KRAS activation is a prominent genetic feature of CRC, KRAS inhibitors do not yield deep or durable responses for the vast majority of CRC patients. For the first time, we have shown that KRASG12X CRC depends on the CBM signalosome for survival, supporting the significant potential of a CBM signalosome inhibitor to transform the treatment landscape of KRASG12C CRC, as well as additional KRAS-associated solid tumors."
"Leveraging our Smart Allostery™ platform, we have developed potent inhibitors of the CBM signalosome complex, with robust in vitro and in vivo data demonstrating apoptosis and tumor growth inhibition and regression in KRASG12C CRC, providing support for the profound clinical potential of a CBM signalosome inhibitor," she added.