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Reposted by Caleb Cheng

Lucid Scientific @lucidscientific.bsky.social · Jun 19

In a recent Nature paper, @djcalebc.bsky.social et al. explore how PIKfyve regulates lysosomal lipid recycling in PDAC. This opens up a therapeutic window: co-inhibition of PIKfyve and the KRAS–MAPK pathway leads to synthetic lethality & tumor regression.

View it here >>> nature.com/articles/s41...

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Reposted by Caleb Cheng

Barbara Marte @barbmarte.bsky.social · May 1

more from last week www.nature.com/articles/s41...

Targeting PIKfyve-driven lipid metabolism in pancreatic cancer - Nature

A study of human and mouse models of pancreatic cancer finds that inhibiting the lipid kinase PIKfyve interferes with the cancer’s lipid homeostasis, making it a potential target for drug development.

www.nature.com

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Caleb Cheng @djcalebc.bsky.social · Apr 28

My team and I are at #AACR25 and have posters to discuss parts of the project (and some future directions) tomorrow! Rüya Pakkan will present on Tuesday AM Abstract #4158 Sec 13 board 8. I will present on Tuesday PM #5384 Sec 12 board 12. Come visit!

Nature @nature.com · Apr 28

Nature research paper: Targeting PIKfyve-driven lipid metabolism in pancreatic cancer

https://go.nature.com/3GmBnvc

Targeting PIKfyve-driven lipid metabolism in pancreatic cancer - Nature

A study of human and mouse models of pancreatic cancer finds that inhibiting the lipid kinase PIKfyve interferes with the cancer’s lipid homeostasis, making it a potential target for drug development.

go.nature.com

Caleb Cheng @djcalebc.bsky.social · Apr 26

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

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Caleb Cheng @djcalebc.bsky.social · Apr 26

Thanks @bryantkl.bsky.social for the shoutout!! Look forward to seeing your future work including target PIKfyve as well as RAS in PDAC 💪

Bryant Lab UNC @bryantkl.bsky.social · Apr 25

Congrats @djcalebc.bsky.social on this tour de force and beautiful study highlighting the important role of PIKfyve in orchestrating lipid metabolism in #pancreatic cancer. Excited by the prospect of a better anti-autophagy target to pair with #RAS inhibitors!

Caleb Cheng @djcalebc.bsky.social · Apr 24

Beyond grateful to share that my main PhD thesis project, Targeting PIKfyve-driven lipid metabolism in pancreatic cancer (@lyssiotislab.bsky.social + Arul Chinnaiyan lab), has just been published in @nature.com!

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Caleb Cheng @djcalebc.bsky.social · Apr 26

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

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Caleb Cheng @djcalebc.bsky.social · Apr 26

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Caleb Cheng @djcalebc.bsky.social · Apr 26

Thanks for this writeup and for highlighting our work!!

Ananya Sen @ana-sen.bsky.social · Apr 24

Pancreatic cancer is a leading cause of cancer-related death. U-M researchers, including @djcalebc.bsky.social and @lyssiotislab.bsky.social, have discovered that simultaneously targeting two key pathways can eliminate tumors.

Learn more about their work in @nature.com at michmed.org/Zx7wD.

Drug targets identified for pancreatic cancer

U-M researchers have discovered that simultaneously targeting PIKfyve and KRAS-MAPK can eliminate tumors in preclinical human and mouse models.

michmed.org

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Caleb Cheng @djcalebc.bsky.social · Apr 26

Thanks so much!!

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Reposted by Caleb Cheng

Lyssiotis Lab @lyssiotislab.bsky.social · Apr 24

🔥Smoking hot new paper and tweetorial from @djcalebc.bsky.social (collab with Chinnaiyan Lab)! 🔥

We are over the moon about this new work and its therapeutic implications for pancreatic cancer. Please have a read and share your thoughts/feedback! 🙏🏼

Caleb Cheng @djcalebc.bsky.social · Apr 24

Beyond grateful to share that my main PhD thesis project, Targeting PIKfyve-driven lipid metabolism in pancreatic cancer (@lyssiotislab.bsky.social + Arul Chinnaiyan lab), has just been published in @nature.com!

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Reposted by Caleb Cheng

Edna Cukierman - Tumor Microenvironment @tme-caf-ecm.bsky.social · Apr 24

Excited to be part of this #AACR25 (@theaacr.bsky.social @rickbuck.bsky.social) Social Media Ambassadorship!!

Look out for updates on the #Tumor-microenvironment ( #TME )-relevant events and highlights. I’ll be posting from Sunday afternoon to midday Wednesday 😎

Vivek Subbiah, MD @viveksubbiah.bsky.social · Apr 24

🚨The #AACR25 buzz is building! I’m thrilled to be a Social Media Ambassador for this year’s #AACR Annual Meeting.
👉🏼Please join me & all the ambassadors as we spotlight the exciting science. Research matters—and so does sharing it. Join the convo with @theaacr.bsky.social @rickbuck.bsky.social

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Caleb Cheng @djcalebc.bsky.social · Apr 24

Thank you for the highlight!!

Wafik S. El-Deiry, MD, PhD, FACP @weldeiry.bsky.social · Apr 24

Targeting PIKfyve-driven lipid metabolism in pancreatic cancer

“targeting PIKfyve and KRAS–MAPK resulted in the elimination of the tumour burden in numerous preclinical human and mouse models”

www.nature.com/articles/s41...

Targeting PIKfyve-driven lipid metabolism in pancreatic cancer - Nature

A study of human and mouse models of pancreatic cancer finds that inhibiting the lipid kinase PIKfyve interferes with the cancer’s lipid homeostasis, making it a potential target for drug development.

www.nature.com

Caleb Cheng @djcalebc.bsky.social · Apr 24

Thanks for the highlight!!!

Christian Frezza @frezzalab.bsky.social · Apr 23

Targeting PIKfyve-driven lipid metabolism in pancreatic cancer

www.nature.com/articles/s41...

Congrats to the @lyssiotislab.bsky.social and all the others involved

Targeting PIKfyve-driven lipid metabolism in pancreatic cancer - Nature

A study of human and mouse models of pancreatic cancer finds that inhibiting the lipid kinase PIKfyve interferes with the cancer’s lipid homeostasis, making it a potential target for drug development.

www.nature.com

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Caleb Cheng @djcalebc.bsky.social · Apr 24

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 💜💜

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Caleb Cheng @djcalebc.bsky.social · Apr 24

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

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Caleb Cheng @djcalebc.bsky.social · Apr 24

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.

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Caleb Cheng @djcalebc.bsky.social · Apr 24

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...

Concurrent Inhibition of the RAS-MAPK Pathway and PIKfyve Is a Therapeutic Strategy for Pancreatic Cancer

PIKfyve inhibition effectively blocks autophagy in multiple models of KRAS-mutant pancreatic cancer and can synergize with inhibitors of members of the RAS–MAPK pathway, providing an effective combina...

aacrjournals.org

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Caleb Cheng @djcalebc.bsky.social · Apr 24

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

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Caleb Cheng @djcalebc.bsky.social · Apr 24

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

a man in a leather jacket is making a funny face while looking at the camera .

ALT: a man in a leather jacket is making a funny face while looking at the camera .

media.tenor.com

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Caleb Cheng @djcalebc.bsky.social · Apr 24

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.

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Caleb Cheng @djcalebc.bsky.social · Apr 24

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!

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Caleb Cheng @djcalebc.bsky.social · Apr 24

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.

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Caleb Cheng @djcalebc.bsky.social · Apr 24

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.

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Caleb Cheng @djcalebc.bsky.social · Apr 24

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!

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Caleb Cheng @djcalebc.bsky.social · Apr 24

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

Targeting PIKfyve-driven lipid metabolism in pancreatic cancer - Nature

A study of human and mouse models of pancreatic cancer finds that inhibiting the lipid kinase PIKfyve interferes with the cancer’s lipid homeostasis, making it a potential target for drug development.

www.nature.com

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