Naoto T Ueno, Director of the University of Hawaii Cancer Center, shared on X:
“My take-home message from AACR Drug Development 2026
ADCs are quietly outgrowing their original job description.
First generation: antibody + cytotoxin, built to widen the therapeutic window on chemo payloads. That’s it-deliver poison more precisely.
What’s emerging now is different: ADCs as the enabling platform for entire drug classes that were previously too systemically toxic to give at all-small molecule inhibitors, degraders, immune payloads. Biparatopic designs improve internalization and payload delivery enough to make tumor-restricted exposure the point, not a side benefit.
That’s the real next generation: the antibody isn’t just a delivery truck for known cytotoxins anymore. It’s what makes an entire new pharmacology usable in the clinic.
RAS drug development just hit its second inflection point. And now there is more to come, and because I am not in this field, I am more confused.
Gen 1: mutant-specific RAS(ON) inhibitors (G12C, G12D, G12V) proved you could drug ‘undruggable’ RAS at all-real responses in NSCLC, PDAC.
Gen 2 is the harder problem: durability. Tumors escape single-mutant blockade by switching RAS states or activating parallel signaling. Multi-selective pan-RAS(ON) agents (daraxonrasib) hit multiple variants at once to close that door.
These are oral, tri-complex inhibitors-small molecules that lock RAS in its inactive state rather than trying to block a shallow binding pocket, which is what made “undruggable” RAS druggable in the first place.
The next level isn’t a better switch-it’s sequencing and combination logic: mutant-selective agents up front, multi-selective coverage for resistance, paired rationally with immunotherapy or chemo based on why a tumor is escaping, not just that it’s escaping.
RAS inhibition is becoming a strategy; this tri-complex approach can be used for other targets.”
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