HRAS

And the most common version of it being switched on in pancreas cancer is in KRAS.

But also we see alterations in NRAS and HRAS.

They occur more commonly in melanoma and other malignancies.

So in other words, all of us are walking around with the RAS gene, but those of us without cancer, it's not switched on.

These are rarer alterations, but it also targets the wild-type version of RAS.

And in a small subset of people with pancreas cancer, we won't identify a RAS mutation But this drug also potentially has activity, and that was identified both in preclinical models, so before we get to people, but also to some degree in the RASALUTE-302 trial.

So, yeah, and it also targets not so relevant to pancreas cancer, but other diseases where, you know, development is going to happen, HRAS and NRAS.

And what are those diseases?

It's mutated in over 90% of pancreatic cancers, about 30% of colorectal cancers.

And you will find RAS mutations, including NRAS and HRAS, almost across the board in cancers.

And so it's a very important oncogene that drives cancer in general.

And, These drugs that we have today actually target RAS, both when it's bound to a GTP, which is in the quote unquote off form, as well as when it's bound to GTP, which is its active form.

So sort of family members, sometimes they're called.

So HRAS, NRAS, and KRAS.

They are related to one another.

They're quite similar.

mutation, KRAS G12C specifically, and only covered a very small fraction of pancreatic cancer patients.

Not HRAS, not NRAS, not any of the many other activating mutations that can occur in any of them.

This approval's reach is considerably wider.

It covers all of them, any pancreatic cancer, because virtually all pancreatic cancers have some form of RAS activation.

I understand where this comes from, but the way it's being stated goes way further than what's actually true, in multiple ways.

First, again, the real, well-documented mechanism here is that daraxanracib doesn't require any one specific mutation the way that the earlier drugs did.

Published structural and biochemical work shows that it binds the active, or on, state of KRAS, HRAS, and NRAS, mutant or wild type, through that cyclophilin A tricomplex we covered in that earlier episode.

Now, It's already been shown to be active against mutations at all three of the major RAS hotspots, position 12, position 13, and position 61, and it probably will be active against virtually all others across all three RAS genes.

It really struggles to risk stratify nodules that are driven by the RAS family of mutations.

You mean HRAS, KRAS and NRAS?

Exactly.

Clinical studies have shown there is no statistically significant difference in the actual rate of carcinoma diagnosis between ThyraMIR positive and ThyraMIR negative RAS-mutated nodules.

So that combination is definitely a fast track to a total thyroidectomy, no questions asked.

Absolutely.

But on the exact opposite end of the frustration spectrum, we have the RAS family of mutations, HRAS, KRAS and NRAS.

I feel like these are just the bane of my existence in clinic.

And, um, but yes, very, very interesting.

Um, Also, hitting the other Ras proteins, H-Ras and N-Ras, is most likely why patients suffer from rash on the drug, because inhibiting this pathway with generic pro-fat inhibitors like EGF receptor and so on, they cause rash.

So that's probably a result of hitting the other Ras proteins, H-Ras and N-Ras.

But then there's another argument that says, well, okay, it has more side effects, but hitting the wild-type HRAS and NRAS may help kill the

tumor.