A Lost Gene Leaves Cancer Cells Dependent on a Ribosome Rescue System

When a cancer cell loses a section of a chromosome, the deletion may remove more than the tumor-suppressor gene that originally stood in its way. Neighboring genes often disappear as collateral damage. Some of those losses create vulnerabilities that were not present before.

One such vulnerability involves FOCAD, a gene missing from roughly one-third of tumors that have also lost the nearby MTAP gene. Without FOCAD, cells become less able to manage errors arising during the translation of genetic instructions and increasingly dependent on a backup system that rescues stalled ribosomes.

Ribosomes are the molecular machines that build proteins from messenger RNA templates. When a ribosome stalls on a faulty or damaged RNA molecule, a complex formed by HBS1L and PELO helps release and recycle it.

The experimental compound TNG961 was designed to remove that rescue system.

A molecule that sends its target for disposal

TNG961 is a molecular glue degrader. Rather than simply occupying and inhibiting a protein, it brings that protein into contact with the cell’s disposal machinery.

The compound binds HBS1L and recruits it to cereblon, part of an E3 ubiquitin ligase complex. HBS1L is then tagged with ubiquitin and destroyed by the proteasome.

The researchers arrived at TNG961 by screening a focused chemical library, identifying a weak starting compound, and optimizing it using cryo-electron microscopy and proteome-wide selectivity studies. The resulting molecule preferentially degraded HBS1L while sparing the closely related protein GSPT1 and several other known cereblon targets.

Loss of HBS1L disrupted its functional partnership with PELO. In FOCAD-deficient cancer cells, this caused protein translation to stall, activated cellular stress responses, and reduced cell viability. Cells retaining FOCAD were considerably less sensitive.

Tumors regressed in several mouse models

The compound was tested in cancer cell lines and in mice carrying transplanted human tumors. These xenograft models can demonstrate drug activity in a living organism, but they do not fully reproduce a patient’s tumor or immune system.

Oral TNG961 produced dose-dependent degradation of HBS1L in tumor tissue. Across four presented models—acute lymphoblastic leukemia, pancreatic ductal adenocarcinoma, and two non-small cell lung cancer models—treatment slowed tumor growth or caused tumors to shrink. Complete regression was reported in selected pancreatic and lung cancer models during approximately three to four weeks of treatment.

TNG961 also remained active in a pancreatic cancer model that progressed during treatment with a PRMT5 inhibitor. After the animals were switched to TNG961, tumor volume declined over an experiment lasting about 50 days. The result suggests that the two approaches exploit different vulnerabilities, although the resistance experiment involved a single preclinical model.

Combining TNG961 with a PRMT5 inhibitor also produced stronger antitumor activity in a lung cancer model. This does not yet establish whether the combination will be safe or more effective than either treatment alone in patients.

There are no human efficacy data yet

The study was entirely preclinical. It combined chemical screening, structural biology, proteomics, cancer-cell experiments, and xenograft studies. It therefore provides no clinical response rate, duration of response, progression-free survival, overall survival, or patient safety data.

The developers also conducted 14- and 28-day toxicology studies in rats and nonhuman primates. In the company’s official AACR presentation, the observed findings were described as minimal, reversible, and monitorable, with no identified central nervous system, cardiovascular, or respiratory safety signals at the tested dose levels. These results support entry into a first-in-human study but cannot predict safety in patients with certainty.

TNG961 illustrates how the loss of a large chromosomal region can be turned into a selective therapeutic opportunity. By discarding genes it no longer needs, a cancer cell may also discard one of its backup systems.