Next time someone says "oh yeah? what did proteomics do to really help someone?" I got you.
Confused? Okay -- so until right before the pandemic, if you heard you had cancer with a KRAS mutation, it was bad. Real bad. Pancreatic cancer is primarily KRAS mutation driven. But Amgen did the unthinkable and targeted the untargetable KRAS mutant proteoforms. And based on their design (AMG510 -- which became sotorasib) lots of drugs are coming.
Here is the problem. Like any drug on any complex thing resistance popped up.
They did exactly what you should do to study drug resistance.
They low-dosed cells in culture and pulled proteomic samples over a long time course (for real, it's really beautiful work, this study has been on my desktop for almost 2 years and read multiple times).
The used a Fusion 2 for the TMT, but I (and now I forget) I think it is MS2 based quan (but maybe MS3 based for the TMTPhospho). But they came up with 3 really interesting proteins. One of which was SHP2.
When they inhibited these 3 proteins -- cells lost their resistance to sotorasib!
That FDA link above? A combination of the SHP2 inhibitor (BBP-398) + Sotorasib. This study is only two years old and it led to a fast tracked combinatorial therapy to help patients!
If someone else found these resistance mechanisms first I sure haven't heard about and I feel pretty plugged in to this scene (who knows with pharma people and their secrets). But I think this is the study that found this!
Proteomics (done well) can help people right now!
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