So the way I looked at it was, this is how kinases work, over there on the left. Kinases bind ATP. They transfer phosphate in a case of tyrosine kinases to tyrosine residues on proteins. And it's these tyrosine phosphorylated proteins that cause white cells to grow uncontrollably.
And this entire field of protein phosphorylation-- a post-translational modification of proteins-- that put phosphate onto specific residues-- tyrosine kinase-- putting phosphate onto tyrosine residuee-- allowed you to begin to think about, could you develop a specific therapy for this molecular abnormality?
And the hypothesis with this trial was that the cancer cells would be more susceptible to DNA damage from the chemotherapy. This kinase inhibitor would prevent this DNA repair from happening in the cancer cells selectively, and that would thus enhance the effects of the chemotherapy. And it was a good idea.
stove the whole bit but anyway um uh so I come from a family of soup Shaman and then um when I was in kinary school I really um I gravitated to soups
So I got into this field right around '85, when all these things were coming together. And I looked at-- I was working on kinase at the time and thought, here's a disease I know is caused by kinase. I should be working on it.
We knew from animal models if you put this oncogene into mice, they get leukemia. And we know that it functions as an activated intracellular kinase. And one of the first laboratory experiments I did was I made a mutation in this kinase-- made it kinase inactive-- and it didn't work.
And so with Los Angeles, I was able to speak with the daughter of the owner-- or the founder of the Phoenix Bakery, at the Asian grocery store, or getting kinako, which is like a Japanese soybean powder,
And then, we had the problem of toxicity. So even if we could get a drug against a couple of kinases, the view was the early knockout mice of individual kinases were embryonic lethal. So even if you shut down one kinase, the view was, you're going to kill people.
What they did is they took 1,000 cancer samples-- some tumors, some cell lines that were tumors that they now had growing on plastic-- and they sequenced a common pathway that's activated in cancer called the MAP kinase pathway. And then what they were looking for was genes that hadn't been known to be mutated that were mutated in these tumors commonly.
And we know that it functions as an activated intracellular kinase. And one of the first laboratory experiments I did was I made a mutation in this kinase-- made it kinase inactive-- and it didn't work. So I saw this as pretty simple, straightforward.
And targeting this probably won't work. So the way I looked at it was, this is how kinases work, over there on the left. Kinases bind ATP. They transfer phosphate in a case of tyrosine kinases to tyrosine residues on proteins.
We had worked together. His company's group at Novartis had synthesized a handful of drugs that seemed to shut down a variety of kinases. And in 1993, they sent me a handful of their compounds for testing.
But there were lots and lots of reasons this drug never should have been developed. First of all, the prevailing view was you could never make a drug against a kinase. The prevailing view in the world was, I just showed you something that binds ATP.
So even if we could get a drug against a couple of kinases, the view was the early knockout mice of individual kinases were embryonic lethal. So even if you shut down one kinase, the view was, you're going to kill people. And that's not a drug we ever want to take a risk on.
We looked to see which ones had BRAF mutations, which ones had a mutation upstream called RAS that had already been discovered a few years prior, and then which ones had activation of this, what's called MAP kinase pathway, but due to upstream activation. And what we found in the laboratory was that these tumors that had BRAF mutations were selectively dependant upon BRAF.
And so she ultimately again, for no particular reason other than it was an open study at the time, was enrolled on the study of a chemotherapy called Irinotecan, and a second drug called AZD7762, which is an inhibitor of a kinase-- or an enzyme, you could say-- within the cell that's important for DNA repair and checkpoint to allow for DNA repair.