Biology subjects

Takebe, N.

Publications and source records attributed to Takebe, N..

2 recordsLinked to original sources

bioRxiv2024

Combinations of RAS pathway inhibitors with targeted agents are active in spheroids of patient-derived cells with oncogenic KRAS variants from multiple cancer types

The KRAS gene is among the most frequently altered genes in cancer and the KRAS protein was long deemed undruggable. Recent strategies to target oncogenic KRAS have included both direct inhibition of the KRAS protein and indirect inhibition of its activity by targeting upstream and downstream signaling pathway mediators. A high-throughput screen of multi-cell type tumor spheroids was designed to identify active combinations of targeted small molecules and KRAS pathway inhibitors. Inhibitors of the non-receptor protein tyrosine phosphatase SHP2 and the guanine nucleotide exchange factor SOS1 were tested to evaluate indirect upstream pathway inhibition, while sotorasib directly inhibited the KRAS G12C variant. As single agents, sotorasib and the SHP2 inhibitor batoprotafib (TNO155) exhibited selectivity towards spheroids with KRAS G12C, whereas the SOS1 inhibitor BI-3406 showed varying activity across KRAS variants. Vertical inhibition of the RAS/MEK/ERK pathway by targeting SHP2 or SOS1 and the downstream kinases MEK (trametinib) or ERK (temuterkib) was highly effective. Inhibition of upstream tyrosine receptor kinases with nintedanib in combination with batoprotafib or BI-3406 was also effective, and in combination with sotorasib, demonstrated synergy in spheroids harboring KRAS G12C. Dual inhibition of the RAS/MEK/ERK and PI3K/AKT/mTOR pathways with batoprotafib or sotorasib with either the mTORC1/2 inhibitor sapanisertib or the AKT inhibitor ipatasertib demonstrated combination activity, primarily in spheroids harboring KRAS G12C. Combination of the BCL-2 inhibitor venetoclax with sotorasib, batoprotafib or BI-3406 resulted in additive and synergistic cytotoxicity. Lastly, concurrent inhibition of the KRAS pathway with sotorasib and batoprotafib demonstrated combination activity in spheroids containing KRAS G12C. SIGNIFICANCEKRAS variants are oncogenic drivers for a range of human cancers. Multiple combinations of small molecule agents that target RAS signaling were screened and reduced the viability of multi-cell type spheroid models for a variety of human solid tumors. Combinations warranting further testing were identified.

cancer biology↗

bioRxiv2024

Drug combinations with apoptosis pathway targeted agents alrizomadlin, pelcitoclax, and dasminapant in multi-cell type tumor spheroids

Apoptosis, or programmed cell death, plays a critical role in maintaining tissue homeostasis by eliminating damaged or abnormal cells. Dysregulation of apoptosis pathways is a hallmark of cancer, allowing malignant cells to evade cell death and proliferate uncontrollably. Targeting apoptosis pathways has emerged as a promising therapeutic strategy in cancer treatment, aiming to restore the balance between cell survival and death. In this context, the MDM2 inhibitor alrizomadlin, the Bcl-2/Bcl-xL inhibitor pelcitoclax, and the IAP family inhibitor dasminapant were evaluated both individually and in combination with standard of care and investigational anticancer small molecules with a spheroid model of solid tumors. The multi-cell type tumor spheroids were grown from endothelial cells and mesenchymal stem cells combined with human malignant cells that were either established or patient-derived cell lines from the NCI Patient- Derived Models Repository. The malignant cell lines were derived from a range of solid tumors including uterine carcinosarcoma, synovial sarcoma, rhabdomyosarcoma, soft tissue sarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor (MPNST), pancreas, ovary, colon, breast, and small cell lung cancer. Interactions were observed from combinations of the apoptosis pathway targeted agents. Additionally, interactions were observed from combinations of the apoptosis pathway targeted agents with other agents, including PARP inhibitors, the XPO1 inhibitor eltanexor, and the PI3K inhibitor copanlisib. Enhanced activity was also observed from combinations of the apoptosis pathway targeted agents with MAPK pathway targeted agents, including the MEK inhibitor cobimetinib as well as adagrasib and MRTX1133, which specifically target the KRAS G12C and G12D variants, respectively. SIGNIFICANCEMulti-cell type tumor spheroids grown from normal and patient-derived malignant cell lines were screened to identify potentially efficacious combinations with the investigational agents alrizomadlin, pelcitoclax or dasminapant that target cell death pathways. This article highlights novel combinations with FDA approved drugs including eltanexor, cobimetinib and copanlisib.

cancer biology↗