Boundless Bio Presents Data on the Role of Extrachromosomal DNA (ecDNA) in Mediating Resistance to Targeted Therapies at the American Association for Cancer Research (AACR) Annual Meeting 2021

The study validates that ecDNA is a driver of cancer by providing a fitness advantage for tumor cells through oncogene copy number amplification and oncogene dependency switching

SAN DIEGO--(BUSINESS WIRE)-- Boundless Bio, a next-generation precision oncology company developing innovative therapeutics directed against extrachromosomal DNA (ecDNA) in aggressive cancers, today will present data at the 2021 American Association for Cancer Research (AACR) Annual Meeting. The poster, Extrachromosomal DNA (ecDNA)-driven switching of oncogene dependency facilitates resistance to targeted therapy, is available to registered attendees today, from 8:30 a.m. – 11:59 p.m. ET. AACR is being held virtually this year due to COVID-19.

“The oncology field has long known that tumors with oncogene amplification are aggressive, lead to a poor prognosis, and are very difficult to treat,” said Zachary Hornby, President and Chief Executive Officer of Boundless Bio. “This study provides rationale for why patients with oncogene amplified tumors have not benefited from targeted therapies. We have demonstrated that ecDNA facilitate a powerful evasive mechanism of switching driver oncogenes when under targeted therapeutic pressure, thereby rendering targeted therapies futile against ecDNA-enabled, gene amplified cancers. Our findings underscore an urgent need and Boundless Bio’s focus in developing precision medicines targeting the underlying vulnerabilities of ecDNA.”

Study Summary

Oncogenes are frequently amplified on ecDNA, circular units of DNA that are separate from chromosomes and that are highly transcribed. Because ecDNA lack centromeres, during mitosis they are passed to daughter cells asymmetrically and can thereby lead to exponential increase in copy number of genes encoded on ecDNA, which in turn facilitates tremendous genomic heterogeneity in tumor cells. The tumor heterogeneity and plasticity enabled by ecDNA can provide a mechanism of resistance for cancer cells against cancer treatment. The study set out to understand the role of ecDNA in facilitating poor responses to targeted therapies in gene amplified cancer.

The study employed the SNU16 gastric cancer model, which contains MYC and FGFR2 amplification at baseline, to characterize ecDNA content, genomic heterogeneity, and ecDNA kinetics in forming resistance to targeted therapy. Boundless Bio scientists performed a longitudinal assessment of cellular resistance and ecDNA dynamics, initially in response to the FGFR2 inhibitor, infigratinib. Upon identifying EGFR amplification on ecDNA as the dominant mechanism of resistance to infigratinib, the study subsequently also evaluated response and resistance to the EGFR inhibitor, erlotinib, delivered either sequentially or in parallel with infigratinib.

The results from the study show differential and dose-dependent resistance of SNU16 cells to infigratinib driven by the heterogeneity of oncogenes residing on ecDNA. First, low doses of infigratinib led to additional amplification of FGFR2 on ecDNA that resulted in levels of FGFR2 that were able to outcompete the drug exposure. High doses of infigratinib resulted in amplification of a new oncogene, EGFR, on ecDNA, representing an ecDNA-mediated switching of oncogene dependency from FGFR2 to EGFR. Next, upon exposing the infigratinib resistant cells (now with EGFR amplification on ecDNA) to single agent EGFR inhibitor, erlotinib, the cells again became resistant, as the emergent ecDNA-enabled EGFR dependency switched back to the original FGFR2 dependency, again via amplification on ecDNA. Lastly, the study tested dual upfront inhibition of both FGFR2 and EGFR with infigratinib and erlotinib, respectively, in previously untreated SNU16 cells. Although initial cytotoxicity was more robust than with either agent alone, the cell population inevitably became resistant. Remarkably, resistance to the up-front dual blockade was also driven by ecDNA, with amplification of various oncogenes, including MET and KRAS, on ecDNA.

This study and its results build upon and confirm previous studies that observe similar dynamics of ecDNA-driven amplification under therapeutic pressure. Such findings help explain the lack of responses and short durations associated with treatment of gene amplified cancers with targeted therapies in the clinic. The inability to a priori predict which new oncogenes would amplify on ecDNA as a mechanism of resistance to single-agent or multi-target inhibition suggest that both sequential and combination approaches of oncogene targeted therapies are suboptimal, if not largely ineffective clinical strategies for patients with ecDNA-driven cancers. These findings highlight the urgent need to take a new therapeutic approach, one that disables the underlying ecDNA machinery used by the tumor cell to drive tumor growth and resistance.

About ecDNA

Extrachromosomal DNA, or ecDNA, are distinct circular units of DNA lacking centromeres but containing functional genes, including oncogenes, that are separated from tumor cell chromosomes. ecDNA replicate within cancer cells and can be passed to daughter cells asymmetrically during cell division, thereby constituting a primary driver of focal gene amplification and copy number heterogeneity in cancer. By leveraging the plasticity afforded by ecDNA, cancer has the ability to increase or decrease copy number of select oncogenes located on ecDNA to enable survival under selective pressures, including chemotherapy, targeted therapy, immunotherapy, or radiation, making ecDNA one of cancer cells’ primary mechanisms of 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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