An Overview of KRAS Tumor Biology


Benjamin P. Levy, MD: David, KRAS has clearly become more relevant in terms of informing us on treatment decisions, and certain data that have emerged over the past 6 to 12 months have altered how we think about this. But perhaps the development of these drugs is predicated on a better understanding of KRAS tumor biology. Now, we learned a lot about this over the years, but certainly as new therapies become available, we’ve learned more. Can you briefly walk us through a high-level overview of KRAS tumor biology 101, if you will?

David R. Gandara, MD: The first thing to say is that KRAS was the first mutation identified in cancer, and clearly the first oncogenic driver. If we go back to 101, we have oncogenes and we have tumor suppressor genes. I love the analogy about oncogenes being your foot stuck on the gas, and tumor suppressor genes being brakes. When you lose the tumor suppressor gene, you have no brakes. The worst situation is to have an oncogene and loss of a tumor suppressor gene; your accelerator is stuck on the floor and you have no brakes.

That being said, KRAS is an oncogene that is a driver. It’s associated with increased proliferation, and it specifically undergoes a transition alternating between GDP [guanosine diphosphate] and GTP [guanosine triphosphate]. When it’s in the GTP state, it is on, and it’s on all the time and it drives the growth of that tumor.

The second thing to mention is that not all KRAS mutations are the same. The worst KRAS mutations tend to be transversions versus transitions. Those transversions are the ones associated with tobacco carcinogenesis—G12C fits into that—and we’ll come back to that.

Benjamin P. Levy, MD: That is a nice 101 overview. I like the analogy between the tumor suppressor and the foot on the gas when describing this. Because KRAS signaling is complex and some of the downstream signaling that occurs when KRAS is constitutively active, this lends itself to prior therapeutic approaches to exploit KRAS in lung cancer and some of the pathways involved downstream.

David R. Gandara, MD: Before the recent advent of small-molecule inhibitors, which directly inhibit KRAS, one approach was to go after the downstream pathway since you couldn’t inhibit KRAS by itself. That’s the MAP kinase pathway. That’s RAS, RAF, and MEK. There are several targets there for which we’ve had drugs that are direct inhibitors before we had these new direct inhibitors of KRAS. These are all genes that are associated, when they’re mutated, with a proliferative state. They are all downstream of KRAS. Once KRAS is on, these other genes become more important.

Benjamin P. Levy, MD: The downstream signaling approach was initially promising with some of these MEK inhibitors—and we can talk about this later—but that certainly didn’t pan out in a phase 3 fashion, at least in a refractory setting. Certainly, MEK inhibition seemed promising and may still seem promising for the future, but at least combined with docetaxel, it didn’t seem to provide a better outcome for KRAS-mutated patients.

Transcript edited for clarity.

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