What Conn eventually understood was that the pairs of mutations that controlled the expression of MYC and PTEN, when put together, also activated something called "the unfolded protein response" at cellular level.
This response allows the cancer cells to become resistant to cellular stress by lowering the levels protein synthesis. It does that by turning a protein called eIF2a, which helps to facilitate protein production, into a different kind of protein called P-eIF2a. This has the opposite effect: to downregulate synthesis.
Further analyses conducted on human prostate cancer tumors revealed that high levels of P-eIF2a were a strong predictor of negative health outcomes in patients with resilient forms of cancer.
So, the researchers decided to go ahead and test if blocking P-eIF2a production would change the cancer cells' response to cellular stress and render them vulnerable to cell death.
They collaborated with Peter Walter, also from the UCSF, whose own team of researchers found that a molecule referred to as the integrated stress response inhibitor (ISRIB) can reverse the effects of P-eIF2a.
ISRIB had not previously been considered as a useful tool in cancer treatment. Instead, Walter and his laboratory used it as a drug that could reverse the impact of severe brain damage in rodents.
The mechanism by which it does this, however, is probably by upregulating protein synthesis in affected neurons.