Dow Lab

Genetic mechanisms of resistance to targeted KRAS inhibition KRAS mutations are among the most prevalent oncogenic drivers in non-small cell lung cancer (NSCLC), yet the mechanisms of therapeutic resistance to KRAS inhibitors in these cancers remains poorly und...

No time for a #bluetorial today, but happy to share a new preprint from the lab. In this paper we used gene saturation and cancer-mutation-focused base editing screens to unveil genetic drivers of resistance to multiple KRAS inhibitors. www.biorxiv.org/content/10.1...

04.08.2025 20:15 — 👍 2    🔁 0    💬 0    📌 0

I promise this is a science account and we have multiple papers brewing, but for now… latest guitar is finished!! This one is my own design and built entirely from scratch. Took ~6 months as my real job kept getting in the way…

17.06.2025 21:31 — 👍 1    🔁 0    💬 0    📌 0

This is amazing!!

14.03.2025 23:01 — 👍 1    🔁 0    💬 0    📌 0

a close up of a man 's face with the words care to share below him ALT: a close up of a man 's face with the words care to share below him

Huge thanks to everyone who contributed to this work over the years, including many of whom are not on bsky... as I wasn't until last week 😬. Also, since I'm a newbie here, please share widely!!

12.03.2025 16:08 — 👍 0    🔁 0    💬 0    📌 0

The selective profile was maintained over 3 weeks of drug exposure and we saw equivalent selective growth inhibition of APC/KRAS/p53 mutant organoids. TLDR: the small molecule shows activity in all WNT-dependent contexts, provided TNKS is lost (het or hom).

12.03.2025 16:08 — 👍 1    🔁 0    💬 1    📌 0

Similar story when you look at organoid growth. The lead molecule (TDI-012804) shows anti-proliferative activity in both TNKS knockout and heterozygous cells (hets having an intermediate response compared to WT).

12.03.2025 16:08 — 👍 1    🔁 0    💬 1    📌 0

In APC-mutant intestinal organoids, the molecule performs very well, inducing a classic pan-TNKS inhibitor (G007-LK) transcriptional response in TNKS knockout cells, but having virtually no effect in the TNKS WT context

12.03.2025 16:08 — 👍 0    🔁 0    💬 1    📌 0

With amazing support from Brandon Malone and Rich Hite at @mskcancercenter.bsky.social, we resolved the cryoEM structure of the lead molecule bound to TNKS2 and propose a mechanism for the preferential binding of this compound to TNKS2 over TNKS1

12.03.2025 16:08 — 👍 0    🔁 0    💬 1    📌 0

So, Jill teamed up with the TRI-I Therapeutics Discovery Institute at @weillcornell.bsky.social and using structure-guided design, generated and individually screened hundreds of compounds. Ultimately, she found a handful of potent and selective molecules

12.03.2025 16:08 — 👍 0    🔁 0    💬 1    📌 0

Turns out that the TNKS locus is on the short arm of chromosome 8, which is frequently lost in advanced epithelial cancers. The hets also show reduced expression, which would theoretically make them sensitive to TNKS2 blockade. Unfortunately, there were no good TNKS2 selective compounds...

12.03.2025 16:08 — 👍 0    🔁 0    💬 1    📌 0

a little girl is asking why not both while standing in a kitchen . ALT: a little girl is asking why not both while standing in a kitchen .

The whole thing started after an accidental and surprising discovery that some cancer cell lines show a molecular response to silencing of the TNKS2 enzyme, whereas most require suppression of both TNKS1 and TNKS2...

12.03.2025 16:08 — 👍 1    🔁 0    💬 1    📌 0

A potent and selective TNKS2 inhibitor for tumor-selective WNT suppression Hyperactive WNT signaling is a potent cancer driver, but clinical translation of WNT inhibitors has been hampered on-target toxicities. WNT signaling can be constrained through inhibition of the PARP ...

New preprint time!!

This one has been brewing in the lab for ~8 years describes a strategy for tumor selective WNT suppression. It was led by an amazing (then) grad student, Jill Zimmerman, with help from a host of lab members and collaborators along the way.

www.biorxiv.org/content/10.1...

12.03.2025 16:08 — 👍 10    🔁 2    💬 1    📌 0

More pics for @chrmosimann.bsky.social @wbderry.bsky.social @lucksmith.bsky.social

Still have to carve the neck, and sand for days, but almost ready for finish! Excited to hear this one - the tap tone sounds really nice!

09.03.2025 12:14 — 👍 5    🔁 0    💬 3    📌 0

On the old bird app, I promised to post updates on the latest guitar build… I failed, but will make up for lost time here. This one is a custom design, larger body (modified grand symphony), koa top back and sides, ebony binding and fretboard, and a bunch of abalone (for the Hawaiian island vibe).

09.03.2025 12:14 — 👍 8    🔁 0    💬 2    📌 0

a man wearing glasses and a jacket is standing in a doorway and says `` oh , hello , professor . '' ALT: a man wearing glasses and a jacket is standing in a doorway and says `` oh , hello , professor . ''

Hello, bsky! First post is fun one - Today I moved to Professor with tenure at @weillcornell.bsky.social! Huge thanks to everyone who has contributed to our efforts over the last decade. It takes a village! Looking forward to more science and guitar building posts on #newoldtwitter.

08.03.2025 00:23 — 👍 15    🔁 0    💬 6    📌 1