Scientists have discovered a new drug which may inhibit the growth of cancer cells by zeroing in on mutated nuclear receptors that promote tumours. The anti-cancer agent could have broad therapeutic applications as it prevents activation of the PI3K pathway, which is common to many cancers. “K-80003 binds specifically to a truncated form of the retinoid X receptor-alpha (tRXRa) protein that promotes tumours,” said Xaio-kun Zhang, professor at Sanford Burnham Prebys Medical Discovery Institute (SBP) in the US. “When it binds tRXRa, it freezes the protein into an inactive (tetrameric) configuration that prevents it from stimulating the PI3K pathway,” said Zhang.
“We wanted to visualise how tRXRa and K-80003 physically interact – at atomic resolution – in a way that makes this such a promising cancer drug,” said Zhang. Working with the lab of Robert Liddington, professor at SBP, the research team used X-ray crystallography to find that six molecules of K-80003 bound to the tetramer interfaces. “Our findings show that K-80003 creates a configuration that locks the tetramer into a tight ball, hiding all of its binding sites so it can not trigger the PI3K pathway,” said Liddington. “We know tRXRa protein is specifically produced by tumour cells, while normal cells only produce full-length RXRa protein. Taken together, our findings explain the drug’s potency and specificity for cancer cells and why the compound has such low toxicity,” Zhang added.
Because RXRa is a nuclear receptor, it has the ability to control gene expression. The mutation that creates tRXRa puts the protein into overdrive, activating PI3K in the cytoplasm and accelerating tumour growth. The team also found an LxxLL motif (a common sequence of amino acids) in the p85a protein, which acts as an intermediary between RXRa and PI3K. Identifying LxxLL sheds new light on how tRXRa binds to the cytoplasmic p85a protein and activates PI3K. When tRXRa becomes a tetramer, p85a can no longer bind to it. These findings also help illustrate how nuclear receptors can function outside the nucleus, and how changes in both conformation and location can dramatically alter their function. “The tRXRa protein is produced in almost all cancers, so the compound could be very effective for many different types, such as breast, liver and colon,” said Zhang. The study was published in the journal Nature Communications.