Outfoxing lung cancer
        To observe whether the cancer cells were able to navigate around this new roadblock, the team let the animals live longer to see what happened next.
As Kalaany explains, “Sure enough, at around 16 weeks, we started seeing some tumours. So, then we asked, how were these tumour cells able to overcome loss of Irs1 and Irs2?”
The answer was found in the levels of essential cellular building blocks: amino acids. Tumour cells lacking the adaptor proteins failed to move amino acids into their cells, despite a plentiful supply outside of the cell.
“Growth factors, like IGF-1, tell cells that nutrients are around,” says Kalaany, “so when you suppress their signalling, the tumour cells don’t take up the amino acids and think they are starved.”
“But we found that the tumour cells can compensate for this and break down their own proteins to generate amino acids.”
So, the KRAS-driven tumours threw out a curve ball: they had, once again, figured out a workaround. By breaking themselves down — in a process known as autophagy — they can generate the raw material they need to thrive.
The researchers, however, were one step ahead.
Heading cancer off at the pass
.        Drugs that inhibit protein breakdown are already available. These include chloroquine, which is currently involved in a number of cancer drug trials, and bortezomib, which blocks proteasomes (protein-digesting structures) and is already used to treat myeloma.
When the two prongs of the attack were combined, the results were more than encouraging. They found that tumour cells lacking Irs1 and Irs2 did not grow well, and, when the inhibitors were added, growth stopped almost completely.
Additional studies will now be needed to understand how these two drug types might interact in a patient. However, this is a considerable breakthrough, and the researchers are excited to take it to the next phase.
“Our work tries to identify metabolic dependencies and vulnerabilities in tumours,” says Kalaany. “If we identify collaborators, we would love to have a clinical trial in non-small-cell lung cancer combining IGF-1 inhibitors with autophagy inhibitors or proteasome inhibitors.”
By testing to breaking point every part of a tumour cell’s survival kit, researchers will, one day, beat cancer.