Thank you!! And thank you for all your help and support along the way 😊

Thanks so much Siva!!! Look forward to seeing yours out soon 🫡

🫶

Thanks so much!!

13/ Finally thanks to the many friends for your support from both @lyssiotislab.bsky.social and the Chinnaiyan lab @brandontwchen.bsky.social @radykm.bsky.social @juliaugras.bsky.social @ja-nietocarrion.bsky.social @mruckert.bsky.social @shiva251993.bsky.social @federicadanzi.bsky.social 💜💜

12/ Also very grateful to officially have my first paper out in the pancreatic cancer field! This community has been so welcoming, and I look forward to working on PDAC throughout my training and career! @pancan.bsky.social

11/ THANK YOU to all the many contributors to this project, collaborators, mentors, and leaders. I am so honored to have been a part of this exciting study @awaddomi.bsky.social @lyssiotislab.bsky.social Arul Chinnaiyan and Yuanyuan Qiao.

10/ We’re extremely excited about this potential therapeutic strategy given all the RAS inhibitors coming out. This also complements another recent story showing that PIKfyve inhibition synergizes with RAS-MAPK through disrupting autophagy @bryantkl.bsky.social

aacrjournals.org/cancerres/ar...

We show this concept in efficacy studies using xenografts, orthotopic allografts, and KPC models in which the combo of RAS-MAPK and PIKfyve inhibitors resulted in regression/cures! Thanks especially to @jenmorton.bsky.social @macleanoncology.bsky.social @cruk-si.bsky.social @uofglasgow.bsky.social

8/ These suggest that co-targeting KRAS-MAPK and PIKfyve may result in synergistic effects through opposing effects on lipid metabolism!

7/ We then found that KRAS can regulate de novo lipid synthesis through regulating genes such as FASN and ACC1 through MAPK signaling, and that KRAS-MAPK inhibition partially reverses the transcriptional and metabolic adaptation that PIKfyve inhibition elicits on PDAC cells.

6/ RNA-seq, metabolomics, lipidomics, and stable isotope tracing strongly corroborated these results and suggested that PIKfyve inhibition triggers an adaptive lipogenic transcriptional and metabolic program. Special thanks to Dr. Pietro Morlacchi from Agilent for their help with the lipidomics!

5/ To assess the metabolic effect of inhibiting PIKfyve in PDAC, we ran a metabolism-focused CRISPR screen using PIKfyve inhibition as a selective pressure. The screen strongly demonstrated that PIKfyve inhibition forces PDAC cells rely on de novo lipid biosynthesis.

4/ We started with a GEMM developed by Yuanyuan Qiao demonstrating that loss of Pikfyve slows PDAC development in KC/KPC models while preserving pancreas function. Using a phase 1 cleared inhibitor ESK981, we also found that PIKfyve inhibition slows PDAC development and growth.

3/ Here, we show that inhibiting PIKfyve slows PDAC growth and induces an adaptive lipogenesis that can be blocked by KRAS inhibition. Follow along below for more in-depth tweetorial!

Link to paper: www.nature.com/articles/s41...