Thank you Sean!

Overall, our findings add to the growing evidence of the critical role of APOBEC3 enzymes in tumor evolution and highlight them as targets to prevent or overcome resistance, ultimately improving treatment outcomes.
A lot more data and context in the paper - please check it out. Fin/

We also found that APOBEC3 activity can be detected early, even prior to treatment, suggesting its potential as a predictive biomarker for identifying cancers at risk of developing resistance. 9/

So, can we target APOBEC3 to prevent or delay resistance? Not clinically - yet. But we identified vulnerabilities that could enable use of currently approved therapies for APOBEC3-driven cancers - PIK3CA mutations and high TMB. 8/

We found that APOBEC3 activity drives resistance by inducing characteristic resistance-associated changes shared between our preclinical models and clinical data - the most compelling evidence to date that APOBEC3 causes resistance-driving mutations! 7/

We then painstakingly modeled APOBEC3 mutagenesis in breast cancer cells and confirmed activity through mutational signatures, kataegis, structural variants - mirroring patterns observed in human tumors. These cells acquired rapid resistance to many therapeutic agents. 6/

Strikingly, APOBEC3 signatures were linked to worse outcomes in patients with HR+/HER2- breast cancer receiving 1L ET+CDK4/6i suggesting APOBEC3-driven genomic instability may contribute to resistance to frontline therapies. 5/

We began by analyzing mutational signatures in nearly 4,000 breast cancer samples from the MSK-IMPACT cohort and found that APOBEC3 signatures were not only very common, but also enriched in advanced disease. 4/

We wanted to understand the inherent genomic instability 🧬 in breast cancers that might explain the frequent, complex and diverse patterns of therapy resistance in this disease. 3/

Big thanks to Reuben Harris, Pedram Razavi, Simon Powell, Jorge Reis-Filho, Britta Weigelt for their guidance and to all co-authors for being part of this incredible team effort! Pier Selenica, Anton Safonov, Fresia Pareja, @xrtgenomics.bsky.social 2/

Come see me expand on the role of APOBEC3 mutagenesis in these processes tomorrow morning!

Thank you Marie!!

Grateful to the organizers for recognizing our work and selecting our abstract for the Basic Science Scholar Award! @sabcs.bsky.social

A hugely collaborative team effort under the mentorship of @saratchandarlapaty.bsky.social @mskcancercenter.bsky.social