Using Single-Cell Genomics to Reveal Clonal Diversity Underlying Leukemia Therapy Resistance

Mission Bio, Inc., a pioneer in high-throughput single-cell DNA analysis and precision genomics, has announced the publication of a study demonstrating the power of its Tapestri^® Platform to help predict and prevent cancer progression. The study, published in Cancer Discovery, is the first-ever study using single-cell DNA analysis to reveal how cancer evolves in response to targeted treatment, leading to therapy resistance and disease progression in AML patients.

Although new targeted therapies have been approved to treat AML, drug resistance and disease progression remain a challenge. Single-cell resolution empowers researchers to describe the polyclonality that underlies clinical resistance to targeted agents and, in turn, take steps to better suppress it.

The cancer drug gilteritinib, a FLT3 inhibitor, was recently approved by the FDA for treating relapsed or refractory AML. However, the polyclonality of AML makes therapy resistance a prominent hurdle, as cell populations or clones evolve and acquire mutations that evade the targeted therapy. Current methods in cancer care include traditional bulk next-generation sequencing (NGS), which relies on sample averages and therefore misses the underlying genetic diversity driving the disease and impacting treatment response. To create effective, dynamic therapies, a deep understanding of each tumor’s true heterogeneity and precise resistance mechanisms is paramount.

The study, which was led by researchers from the Abramson Cancer Center at the University of Pennsylvania (Penn) as well as from the University of California San Francisco (UCSF), sought to characterize the clonal evolution of AML at the single-cell level, identifying multiple resistant clones missed by traditional sequencing methods. Leveraging Mission Bio’s high-throughput single-cell targeted DNA sequencing technology, the Tapestri Platform, the lab analyzed retrospective longitudinal sample sets from patients treated on clinical trials. The platform’s unique sensitivity empowered the researchers to monitor the clonal progression of AML in response to targeted therapy with gilteritinib, ultimately revealing pre-existing and treatment-emergent clones that activated the Ras/MAPK signaling pathway, thus driving subsequent therapy resistance in patients.

These insights illuminate not just the need for high-resolution monitoring of patient response to targeted treatment, but also uncover the potential to develop more impactful, dynamic therapies for those with advanced AML.

“Cancer is a dynamic — even ‘smart’ — disease, constantly evolving to evade treatment,” explained co-senior author Dr. Catherine Smith of UCSF. “In monitoring how the disease evolves and develops clinical resistance, we have the potential to apply dynamic therapies that mirror the dynamics of the disease. These findings put us on the precipice of the next frontier of precision medicine.” Dr. Alexander Perl and Dr. Martin Caroll from Penn were also co-senior authors.

“Empowering breakthroughs that can save patient lives is key to our work at Mission Bio,” explained Charlie Silver, co-founder and CEO. “Our Tapestri Platform is uniquely equipped to translate these meaningful discoveries in single-cell genomics to the clinic, and make a real difference in patient care and outcomes.”

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