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👨🏽‍🏫Mini Tweetorial 1👨🏽‍🏫
🧬RAS mutation drives 90+% of #PDAC
Most common mutation is #KRAS G12D or G12V, but a minority of patients have G12C (~3%)

💡In non-RAS mutated disease, higher probability of a gene fusion event as a driver

pubmed.ncbi.nlm.nih.gov/28810144/

#TumorBoardTuesday Mike Pishvaian Integrity CE, LLC Dr. Shubham Pant PanCAN Lustgarten Foundation 6/17 #TumorBoardTuesday
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It has long been a dream to 🎯KRAS!

RAS is a GTPase-when GTP is bound, KRAS is ✅
When GDP is bound, it’s ❌

Normally, we try to drug the pocket where GTP binds–but we can’t easily reach it in KRAS, and the protein binds GTP tightly!

#TumorBoardTuesday Mike Pishvaian Integrity CE, LLC Dr. Shubham Pant PanCAN Lustgarten Foundation 7/17 #TumorBoardTuesday
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@Kevansf & team found a way to build a molecule that irreversibly binds cysteine (G12C), outside of the GTP binding pocket!

This causes 🔗rxn which changes shape of GTP binding pocket. Bottom line: GTP can't bind & KRAS is locked ❌

#TumorBoardTuesday Mike Pishvaian Integrity CE, LLC Dr. Shubham Pant PanCAN Lustgarten Foundation Kevan Shokat NEJM UCSF Helen Diller Family Comprehensive Cancer Ctr KRASKickers 8/17 #TumorBoardTuesday
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Sotorasib= 1st approved KRAS G12C inhibitor. Initial trials in NSCLC, but also with activity in pre-treated G12C mutated #PDAC

✅21% ORR
4.0 mo mPFS
6.9 mo mOS

nejm.org/doi/full/10.10…

#TumorBoardTuesday Mike Pishvaian Integrity CE, LLC Dr. Shubham Pant PanCAN Lustgarten Foundation Kevan Shokat NEJM UCSF Helen Diller Family Comprehensive Cancer Ctr KRASKickers 9/17 #TumorBoardTuesday
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Adagrasib- another covalent G12C inhibitor
Longer t1/2 (24h vs 5.5h) than sotorasib
Improved CNS penetration

In pre-treated #PDAC , ORR 33.3%

ascopubs.org/doi/full/10.12…

#TumorBoardTuesday Mike Pishvaian Integrity CE, LLC Dr. Shubham Pant PanCAN Lustgarten Foundation Kevan Shokat NEJM UCSF Helen Diller Family Comprehensive Cancer Ctr KRASKickers 10/17 #TumorBoardTuesday
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Glecirasib: G12C covalent inhibitor
In pre-treated #PDAC :
ORR 41.9%
mPFS 5.6m
mOS 10.7m

Danger with cross-trial comparison, but are we seeing incremental gains with subsequent generation inhibitors?? No head-to-head studies yet.

#TumorBoardTuesday Mike Pishvaian Integrity CE, LLC Dr. Shubham Pant PanCAN Lustgarten Foundation Kevan Shokat NEJM UCSF Helen Diller Family Comprehensive Cancer Ctr KRASKickers 11/17 #TumorBoardTuesday
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What about the rest of the (more common) KRAS mutations?

Lots of work ongoing now, including inhibitors targeting other muts, including more common mutations found in #PDAC

🔹G12D specific
🔹Pan exon 12
🔹KRAS “on” inhibitors

#TumorBoardTuesday Mike Pishvaian Integrity CE, LLC Dr. Shubham Pant PanCAN Lustgarten Foundation Kevan Shokat NEJM UCSF Helen Diller Family Comprehensive Cancer Ctr KRASKickers 12/17 #TumorBoardTuesday
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Enter MRTX1133= G12D selective small molecule
Clinical trial ongoing now: NCT05737706
Animal data:
🔹Activity in #PDAC
✅Improves immune mediated killing of PDAC + may synergize with checkpoint inhibitors

cell.com/cancer-cell/ab…

#TumorBoardTuesday Mike Pishvaian Integrity CE, LLC Dr. Shubham Pant PanCAN Lustgarten Foundation Kevan Shokat NEJM UCSF Helen Diller Family Comprehensive Cancer Ctr KRASKickers 13/17 #TumorBoardTuesday
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While G12C inhibitors and G12D inhibitors could be revolutionary...
Is there a pan-mutant RAS inhibitor?

RMC 6236 is an example, targeting ALL KRAS G12 mutations.

How does it work? Read on… 👇

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Totally different MOA
RMC 6236 is like a GLUE
Sticks one protein, cyclophilin A, directly onto GTP bound (active) mKRAS.
Similar strat also being used to target KRAS G12C!

The result in PDAC:
Phase I- ORR 20% w some ongoing responses

#TumorBoardTuesday Mike Pishvaian Integrity CE, LLC Dr. Shubham Pant PanCAN Lustgarten Foundation Kevan Shokat NEJM UCSF Helen Diller Family Comprehensive Cancer Ctr KRASKickers 15/17 #TumorBoardTuesday
If we can ❌KRAS, will ❌EGFR at the same time work better?

Active area of research--combos are promising so far!

Adagrasib + cetuximab= DOUBLED ORR in #CRC and now supported in #NCCN
Ongoing work in PDAC