STAT3 protein degraders exhibit anticancer activity by increasing tumor sensitivity to PD-1 inhibitors

Recently, Kymera announced the experimental results of KTX-201, a protein degrader targeting STAT3 protein

STAT3 is a transcription factor that can be activated by different cytokine and growth factor receptors, possibly also by mutations in oncogenic fusion proteins and STAT3 itself

▲STAT3 has multiple roles in tumor survival and growth (Image source: Kymera's official website)

Previously, Kymera found that KTX-201, a protein degrader targeting STAT3, as a single agent, can cause ALK-positive anaplastic large cell lymphoma (ALCL) in vitro and in vivo experiments, as well as NK/T with STAT3 mutants cell lymphoma, and increased growth arrest and cell death in ALK-negative ALCL cell lines

Analysis of the gene expression profiles of KTX-201-treated tumors found that the expression of pro-inflammatory genes, as well as the expression of biomarkers of T-cell activation and M1 macrophage activation, were significantly increased compared with controls

▲KTX-201 changes the tumor microenvironment (Image source: Kymera official website)

Moreover, when KTX-201 was combined with an anti-PD-1 antibody, it resulted in a 60% complete remission in a mouse model of solid tumors, and the animals gained immune memory and the growth of re-implanted tumors was inhibited

▲KTX-201 combined with anti-PD-1 antibody showed better anti-cancer activity (Image source: Kymera official website)

Kymera pointed out that KTX-333, a potential "first-in-class" STAT3 protein degrader currently developed based on KTX-201, is expected to receive IND approval before the end of 2021, and will launch Phase 1 clinical trials in patients with hematological cancers and solid tumors

References:

[1] Targeted STAT3 Degradation Leads to Remodeling of an Immunosuppressive Tumor Microenvironment and Subsequent Sensitization to Immune Checkpoint Inhibition.