Boundless Bio Presents Data on Extrachromosomal DNA (ecDNA) Driven Resistance to KRASG12C Inhibitors at the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics 2021

Oct. 7, 2021 12:00 UTC

Boundless Bio Presents Data on Extrachromosomal DNA (ecDNA) Driven Resistance to KRASG12C Inhibitors at the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics 2021

 
 

SAN DIEGO--(BUSINESS WIRE)-- Boundless Bio a next-generation precision oncology company developing innovative therapeutics directed against extrachromosomal DNA in aggressive cancers, today will present a poster at the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics. The poster, LBA005: Detection of KRAS amplification on extrachromosomal DNA (ecDNA) upon acquired resistance to KRASG12C inhibitors, is available to registered attendees starting at 9AM EST today.

“Over the past decade, targeted therapies have delivered significant health improvement to patients with oncogene-driven cancers, with KRASG12C inhibitors being the most recent example,” said Zachary Hornby, President and Chief Executive Officer of Boundless Bio. “Despite the use of potent inhibitors against oncodrivers like KRAS, resistance inevitably emerges. ecDNA driven oncogene copy number amplifications, a mechanism that is distinct from second site mutations, is a frequent cause of resistance in cancer cells. Boundless Bio, in collaboration with the Dana-Farber Cancer Institute and Mirati Therapeutics, has shown that, in colorectal patients treated with KRASG12C inhibitors, ecDNA based amplification played an important role in resistance to KRASG12C inhibitor therapy. These results further substantiate our mission to develop novel therapeutic strategies that can address ecDNA-enabled cancers.”

“We are pleased to collaborate with Boundless Bio on this important work to identify mechanisms of acquired resistance to KRASG12C inhibitors,” said Dr. Mark Awad, M.D., Ph.D., Assistant Professor of Medicine at Harvard Medical School and Clinical Director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute. “There is mounting evidence that cancers rely on oncogene amplification to drive tumor growth and resistance, and some of this copy number amplification may be occurring on extrachromosomal DNA. The development of innovative therapies for ecDNA-driven cancers will hopefully provide new treatment options for our patients in the future.”

Study Summary

We first confirmed the presence of ecDNA in tumor biopsy samples collected by the Dana-Farber Cancer Institute from clinical trial patients treated with the KRASG12C inhibitor, adagrasib. Analysis of next-generation sequencing (NGS) data using proprietary Boundless Bio software enabled detection of circular DNA structures encompassing the KRAS locus. Consistent with this finding, fluorescence in situ hybridization (FISH) analysis by Boundless Bio scientists confirmed the presence of KRAS amplifications on ecDNA.

Next, an in vivo study was performed to investigate whether resistance to KRASG12C inhibitor monotherapy is mediated through an ecDNA mechanism. We used a genetically modified CT26 murine colorectal cancer model expressing KRASG12C alleles. In line with recent clinical data, both adagrasib and sotorasib induced transient tumor regressions in the CT26 model that subsequently resumed tumor growth following several weeks of continuous therapy. Strikingly, in both adagrasib and sotorasib resistant tumors, bioinformatic analysis of whole-genome sequencing data and FISH analysis from isolated recurrent tumors identified high levels of ecDNA mediated amplification of KRASG12C compared to vehicle-treated samples. The kinetics of KRAS amplification on ecDNA was also determined, showing increased KRAS copy number within two weeks after initiation of KRASG12C inhibitor treatment. Such rapid onset of resistance after tumor regression is consistent with previous in vivo studies with other ecDNA enabled tumor models. Cultures from ex vivo experiments also maintain resistance due to KRAS amplified ecDNA. Collectively, these observations implicate ecDNA as an important mediator of resistance to KRASG12C inhibitor monotherapy.

This study, along with previously published studies, confirm the evasive dynamics of ecDNA-driven oncogene copy number amplification upon therapeutic pressure on oncodrivers such as EGFR, FGFR, and now mutant KRAS. Because ecDNA can be distributed heterogeneously throughout tumors, resistance to targeted therapies can be rapid, aggressive, and difficult to treat. Here we confirm the critical need for novel therapeutic strategies directed to the function of ecDNA within cancer cells and the urgency to bring these therapies to patients with oncogene amplified cancers.

About ecDNA

Extrachromosomal DNA (“ecDNA”) are circular units of nuclear DNA found within cancer cells, and which contain highly transcriptionally active genes, including oncogenes, but are physically distinct from chromosomes and lack centromeres. ecDNA replicate within cancer cells and, due to their lack of centromeres, can be asymmetrically passed to daughter cells during cell division, leading to focal gene amplification and copy number heterogeneity in cancer. By leveraging the plasticity afforded by ecDNA, cancer cells have the ability to increase or decrease copy number of select oncogenes located on ecDNA to enable survival under selective pressures, including targeted therapy, immunotherapy, chemotherapy, or radiation, thereby making ecDNA one of cancer cells’ primary mechanisms of growth, recurrence, and treatment resistance. ecDNA are not found in healthy cells but are present in many solid tumor cancers. They are a key driver of the most aggressive and difficult-to-treat cancers, specifically those characterized by high copy number amplification of oncogenes.

About Boundless Bio

Boundless Bio is a next-generation precision oncology company interrogating a novel area of cancer biology, extrachromosomal DNA (ecDNA), to deliver transformative therapies to patients with previously intractable cancers.

For more information, visit www.boundlessbio.com.

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Contacts

James Lee
Director of Business Development
Boundless Bio
jlee@boundlessbio.com

 
 

Source: Boundless Bio

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