Check out our new study in @ScienceMagazine, where we take on a 100-year-old debate: what’s the role of aneuploidy in cancer?. We discovered that genetically removing extra chromosomes blocks cancer growth - a phenomenon we call “aneuploidy addiction”.

Hypothesis: maybe there's a hypomorphic allele in an essential gene on Chr18 or 19, and trisomies of those chromosomes are selected to raise the dosage of those proteins to wild-type levels? . Link to the paper:

Introducing Grok Imagine.

An unexplained case of Mosaic Variegated Aneuploidy: (1) no mutations in known MVA genes and (2) no true variegation, only chromosomes 18 and 19 are affected. I don't know any germ-line mutations that would cause chromosome-specific aneuploidy. thoughts?

RT @ProfJeffries: Politics does not have to be boring. You can have fun and still make a real difference in people's lives.

RT @emilyriehl: Kudos to Terry Tao for this:.

Next up - we want to improve the tumor-specific accumulation of CDK11 to bypass this toxicity, and we’re looking for other emerging drug targets to create mouse models for. If you’re interested in collaborating, feel free to reach out!.

Along the way, we also learned a ton about the biology of CDK11, the 1p36 locus (one of the most frequently-deleted regions across cancer genomes!), and the CDK-dependent control of gene expression.

If you have a mutation that blocks the interaction between your drug and its target, and so long as that mutation is tolerated in mice, then you can do the same thing that we did - make a mouse with the resistance mutation and see what happens after drug treatment.

I think that this approach can substantially improve the drug development process. Nearly all cancer drugs fail during clinical testing, and toxicity is one of the most common reasons why. We urgently need better approaches to predict and study toxicity in a preclinical setting.

We injected the G568S mice with a mouse cancer cell line and then treated them with a high dose of MEL-495R (which was tolerable to the G568S mice but toxic to WT mice). This resulted in a significant anti-cancer effect, verifying that on-target toxicity limits effective dosing.

This suggested that toxicity (which we believed to be CDK11-dependent) was limiting our ability to effectively dose these mice. To verify this, we returned to our CDK11-G568S mouse strain to tease apart the cause.

This gave us confidence to move forward with the drug. We identified a non-toxic dose of MEL-495R and tested it in several xenografts. However, it showed very little anti-cancer activity. A splicing qPCR indicated that this non-toxic dose wasn’t appreciably inhibiting CDK11.

We bred a large cohort of CDK11-mutant (G568S) and CDK11-WT mice, treated them with an ultra-high dose of MEL-495R, and it worked beautifully. The wild-type mice became very sick while the CDK11-G568S mice were totally fine. Our drug is specific for CDK11 - in living mice!

We thought - if the mice expressing this mutation are still affected by our CDK11 inhibitor, then that tells us that it’s causing CDK11-independent toxicity. In contrast, if these mice are resistant to the drug, then any side effects of the drug in WT mice are due to CDK11.

We came up with a way to answer this question. We had discovered a mutation in CDK11 that blocks drug binding to it. We thought - what if we put that mutation into a mouse? So, we found the mouse ortholog of the human mutation, CRISPR’d it into some zygotes, and did exactly that.

You can throw every biochemical assay in existence against a drug, but that won’t do it - we can’t test all ~20,000 human proteins at once, it’s really hard to determine drug concentrations in each tissue, and in vivo drug metabolism can generate dozens of derivative compounds.

This brought us to an issue that is absolutely crucial for cancer drug development. All cancer drugs have at least some toxicity. If you have a drug against a new target (like CDK11), how do you know if that toxicity is due to CDK11 inhibition or due to something else?.

Now, we wanted to take the drug in vivo. Unfortunately, it had a terrible ADME profile. We worked with the talented chemists at Meliora to develop an improved CDK11 inhibitor, and we created MEL-495R, which exhibits potent CDK11 inhibition and superior PK properties.

This makes CDK11 a new “CYCLOPS” gene, as described by @RameenBeroukhim and Bill Hahn - a vulnerability established when a gene is deleted so that only one copy of that gene remains:

Next, we figured out why - 1p36 is where CDK11 and its activating cyclin (cyclin L) are encoded. Having a lower dosage of these genes enhances the dependency on the remaining enzyme, creating a synthetic-lethal relationship.

For any cancer therapy, finding a biomarker to predict sensitivity is key. We analyzed screening data with CDK11-targeting CRISPR, CDK11-targeting RNAi, and OTS964 treatment, and they all pointed to the same biomarker: Chr1p36 deletions enhance sensitivity to CDK11 ablation.