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/

@saratchandarlapaty.bsky.social expertly summarizing our work on how underlying genomic instability in breast cancer leads to therapy resistance leaving with key ideas on how we might target them! Come see me expand on the role of APOBEC3 mutagenesis in these processes tomorrow morning at #AACR25!

Congratulations to @reikudo.bsky.social for the beautiful work inspiring current+future studies! #SABCS24

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

So honored to have gotten the opportunity to present our work showing a prevalent role of APOBEC3 mutagenesis in driving therapy resistance in breast cancer at #SABCS24!

Congratulations to @caiy0219.bsky.social for an excellent poster presentation today! 👏🏽
Also, so happy to be reunited with @reikudo.bsky.social to represent the translational team in @saratchandarlapaty.bsky.social’s lab at #SABCS2024!