Avantika Gupta

More mechanisms of resistance to anti-HER2 ADCs, this time with a focus on loss of target interaction!

Now online in Cancer Discovery @aacrjournals.bsky.social: Trastuzumab Deruxtecan (T-DXd) Resistance via Loss of HER2 Expression and Binding - by Wanyi Chen, @joshdragomd.bsky.social, @saratchandarlapaty.bsky.social, and colleagues doi.org/10.1158/2159... @mskcancercenter.bsky.social

Thank you Sean!

Amazing to have our work featured on the cover of the latest issue of @natgenet.nature.com! The artwork, like the science, is a collaborative creation with everyone’s fingerprints 🎉
www.nature.com/articles/s41...

Inhibition of NR2F2 restores hormone therapy response to endocrine refractory breast cancers NR2F2 modulates the ER cistrome, coregulator interactions, and chromatin accessibility to promote endocrine resistance in ER+ breast cancer.

Published online today - work led by Yanyan Cai: Inhibition of NR2F2 restores hormone therapy response to endocrine refractory breast cancers | Science Translational Medicine www.science.org/doi/10.1126/...

APOBEC3 mutagenesis drives therapy resistance in breast cancer Nature Genetics - Analysis of a large cohort of metastatic breast cancer samples shows that APOBEC mutational signatures are enriched in post-treatment samples. APOBEC activity was also associated...

Published online today - work from our team led by Avantika Gupta, revealing how APOBEC3 mutagenesis promotes resistance to several targeted therapies in breast cancer. Check it out!

urldefense.com/v3/__https:/...

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/

APOBEC3 mutagenesis drives therapy resistance in breast cancer - Nature Genetics Analysis of a large cohort of metastatic breast cancer samples shows that APOBEC mutational signatures are enriched in post-treatment samples. APOBEC activity was also associated with mutations known ...

So excited to share our latest work with @saratchandarlapaty.bsky.social, Antonio Marra, Andrea Gazzo @mskcancercenter.bsky.social out today in @natgenet.nature.com! We uncover the function and mechanism of APOBEC3-driven therapy resistance in breast cancer. 🧵 1/
www.nature.com/articles/s41...

@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!

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

Thank you Marie!!

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!

APOBEC3 mutagenesis drives therapy resistance in breast cancer Acquired genetic alterations commonly drive resistance to endocrine and targeted therapies in metastatic breast cancer[1][1]–[7][2], however the underlying processes engendering these diverse alterati...

Great work from Dr Avantika Gupta in @saratchandarlapaty.bsky.social lab, linking APOBEC mutagenesis to facilitating therapy resistance in HR+ breast cancer. Lots of intriguing vulnerabilities to target that would be relevant in a lot of breast cancers! #SABCS24

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

Fantastic presentation #SABCS by @avantikagupta.bsky.social on apobec3 in breast cancer. Demonstrating the role of this process in promoting therapy resistance.

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!

@marie-will.bsky.social expertly setting up a major research focus and our latest work identifying a new resistance mechanism and a rational strategy to improve the efficacy of the HER2 #ADC T-DXd.
Please check it out here: www.cell.com/cell-reports...

Thank you for highlighting our work! Excited to see how the combination performs in trials.