Sec61 Inhibition: A Novel Therapeutic Approach for Hematologic Cancers

New research has spotlighted the importance of secreted and membrane proteins in the progression of cancer. These proteins can act as growth factors, signaling receptors, and immune evasion checkpoints. Their synthesis involves the transport of polypeptides into the endoplasmic reticulum (ER) via the Sec61 channel. While there are known inhibitors targeting Sec61 with antitumor effects, they have not been suitable for clinical trials due to pharmaceutical limitations or tolerability issues.

The study introduces a new class of small molecule Sec61 inhibitors that have shown effectiveness against blood-related cancer cells both in laboratory settings and animal models. KZR-8834, a compound identified from a screening process, has demonstrated significant potency against several Sec61-dependent proteins linked to cancer, including immune checkpoint proteins.

In vitro tests on 346 human cancer cell lines revealed that KZR-8834 has a wide-ranging cytotoxic impact on both solid and blood cancers, particularly hematologic malignancies. It showed high potency against various cancers, such as acute lymphoid leukemia, acute myeloid leukemia, lymphoma, and multiple myeloma.

Animal studies using mouse models of multiple myeloma and mantle cell lymphoma indicated that weekly dosing of KZR-8834 or its analog KZR-9261 led to over 90% tumor growth inhibition with minimal toxicity.

To understand the cellular response, two multiple myeloma cell lines were examined: one sensitive and one resistant to KZR-8834. The sensitive cells showed a substantial increase in caspase 3/7 activation and a sharp drop in viability upon exposure to the compound. In contrast, the resistant cells did not exhibit these effects. Further analysis through RNA sequencing and mass spectrometry revealed an immediate increase in ER stress response genes and proteins, along with the activation of the unfolded protein response, particularly in the sensitive cells.

The study concludes that the inhibition of Sec61-dependent protein translocation by these novel small molecules presents a broad antitumor effect, potentially through the induction of proteotoxic stress. The findings suggest a promising new therapeutic approach for blood cancers, with the ER stress response capacity emerging as a potential biomarker for treatment efficacy.