The first Nabet lab paddle boarding outing was a success! Couldn’t be prouder of this amazing group — grateful to lead such a committed, collaborative, and inspiring team.

Standing up for science in Seattle!

11) Finally, our profiling studies highlighted the key role of T cells in these responses, and we evaluated the direct effects of CD8+ or CD4+ T cells. Neutralization of CD8+ T cells largely rescued these responses, highlighting the role of CD8+ T cells in antitumor immunity.

10) Turning to single-cell RNA-seq, we found that KRAS G12V degradation reprogramed the tumor microenvironment to promote antitumor immunity.

9) This result inspired us to use immune profiling to dig deeper. We found that KRAS G12V degradation increased overall immune cell infiltration and increased CD8+ T activity.

8) Our immune-competent model allows us to determine the tumor intrinsic and extrinsic mechanisms leading to tumor regression. Using bulk RNA-sequencing, we observed that acute KRAS G12V degradation led to upregulation of gene signatures associated with the inflammatory and interferon responses.

7) To extend our observations to pancreatic cancer, we turned to an isogenic pancreatic cancer xenograft model. Excitingly, we found that targeted degradation of KRAS G12V effectively decreased tumor burden in this pancreatic cancer model.

6) To evaluate the consequences of prolonged KRAS G12V degradation, we next performed efficacy studies upon dTAG molecule administration. We were thrilled to see remarkable tumor regressions upon KRAS G12V degradation.

5) Gratifyingly, acute administration of dTAG molecules led to effective KRAS G12V degradation in the tumor, collapsing downstream signaling, decreasing proliferation, and increasing cell death.

4) To develop a transgenic dTAG-KRAS G12V mouse model, we designed a targeting vector that included a Lox-Stop-Lox cassette to allow for spatial/temporal control of dTAG-KRAS G12V. We first activated dTAG-KRAS G12V with a Cre recombinase in the lung, resulting in lung adenocarcinoma.

3) Over the years, we have developed several dTAG cellular models to degrade mutant KRAS. Here, we first confirmed that tagging KRAS G12V did not alter protein function. dTAG-KRAS G12V activated signaling, transformed cells, and drove tumor formation, comparable to untagged KRAS G12V.

1) This work was a tremendous collaboration between my lab, @huazhanglab.bsky.social, and Kwok Wong’s lab, and led by Dezhi, Ke, Yuan, Jiajia, and @sauravk05.bsky.social. Special shoutout to Nabet lab members, including Saurav, Annabel, @christinakuismi.bsky.social, Joy, and Mia for their hard work.

🧪 Ready, set, degrade!

So proud to share our work in the @jclinical-invest.bsky.social, establishing a versatile approach for creating transgenic dTAG mice to degrade oncoproteins. We showcase that KRAS G12V degradation triggers antitumor immunity in lung cancer.

Link: www.jci.org/articles/vie...

It’s been a great week having two new postdocs, Brandon Czowksi and David English, join our lab! Super excited to have these amazing scientists join our team to drive new E3 ligase and technology development projects.

Interested in joining the Nabet lab? We are hiring a Research Technician III! With several new grants, we are seeking a lab manager to contribute to our targeted degradation projects and collaborations with academic/industry partners. Please share/apply here: careers-fhcrc.icims.com/jobs/26517/r...

Interested in photoactivatable PROTACs? Check out Christina Kuismi’s commentary in Trends in Pharmacological Sciences on this emerging field. We focus on an innovative class of nanoformulated PROTACs that can achieve target protein degradation in mouse models. authors.elsevier.com/a/1hpjUbg0kk...

#HiSciSky! I am an Assistant Professor at Fred Hutch and my lab is dedicated to targeting oncogenic signaling through the control of protein homeostasis. Our goal is to advance new therapeutics including targeted protein degradation strategies for cancer patients. Looking forward to connecting here!