MSKCC & U. of Miami Researchers Identify BTK Inhibitor-Resistant Clones Using Single-Cell DNA Sequencing from Mission Bio

SOUTH SAN FRANCISCO, Calif., Feb. 24, 2022 /PRNewswire/ -- Mission Bio, the pioneer in high-throughput single-cell DNA and multi-omics analysis, announced the publication of new findings from researchers at Memorial Sloan Kettering Cancer Center (MSKCC) and the University of Miami showing six novel mutations that prevented patients with B-cell leukemia from responding to a new class of non-covalent Bruton's tyrosine kinase (BTK) inhibitors. In the paper, which published today in the New England Journal of Medicine (NEJM), researchers from the labs of Omar Abdel-Wahab, MD, and Justin Taylor, MD, used Mission Bio's Tapestri platform to characterize cancer sample genomes at the single-cell level, thereby identifying mutational patterns in the B cell receptor pathway that could shape future treatment paradigms.

Covalent BTK inhibitors like ibrutinib have been used as a first-line long-term treatment for B cell malignancies like chronic lymphocytic leukemia (CLL) since approval in 2016. But eventually, the majority of patients will develop treatment resistance through a mutation at cysteine residue 481 (C481), where covalent inhibitors bind BTK. To avoid this, a new generation of noncovalent BTK inhibitors is in clinical development with different binding sites. One of them, pirtobrutinib, is currently in late-stage clinical trials for patients with CLL who have failed covalent BTK inhibitors.

In the NEJM paper, the authors confirmed some patients developed resistance to pirtobrutinib, with disease progression seen in 9 of 55 patients with CLL. The researchers performed bulk genomic sequencing on samples from pirtobrutinib-resistant patients to identify resistance-associated mutations. To investigate the evolution of subclones harboring these resistance mutations, the team performed single-cell DNA sequencing on samples taken from two patients before treatment and at relapse (during pirtobrutinib treatment). These studies revealed that both primary (pre-existing) and secondary (acquired) resistance mechanisms were present. For instance, both patients had subclones with an acquired resistance-conferring BTK mutation, and one patient also had a subclone with a resistance-conferring mutation in the substrate PLCγ2 (downstream of BTK) prior to treatment. Notably, the Tapestri Platform allowed the investigators to identify the co-occurring mutations within each subclone, providing a picture of how new subclones evolved from pre-existing ones.

In addition, the authors found that the resistance mutations to this new class of non-covalent BTK inhibitors could also confer resistance to other non-covalent and covalent BTK inhibitors. If patients were screened at the single-cell level to identify mutational patterns like these, it could predict whether they are likely to respond to a BTK inhibitor and hence guide personalized treatment.

"We were detecting these mutations at the time of clinical resistance with conventional bulk NGS. So the question was, were these mutations present at some low degree prior to therapy, and what are the mutation combinations that emerge during therapy that underlie resistance?" said Dr. Abdel-Wahab, Director of the MSKCC Center for Hematologic Malignancies. "Tapestri is the only reliable method right now that can measure mutations at the DNA level in individual cells. It is well-recognized in the hematology field because of how many studies have used it so far."

"This impressive study is the first in humans that describes novel mechanisms of resistance to pirtobrutinib, a very promising drug that is currently in advanced clinical development," said Yan Zhang, PhD, CEO of Mission Bio. "But it's just the latest example of how Tapestri can help discern when treatment-resistance clones emerge, holding the potential to inform the course of therapy. We are proud to support academic researchers and drug development partners to turn findings like these into new ways of treating patients and advancing precision therapeutics."

To learn more about Mission Bio and the Tapestri platform, please visit www.missionbio.com.

About Mission Bio
Mission Bio is a life sciences company that accelerates discoveries and cures for a wide range of diseases by equipping researchers with the tools they need to better measure and predict our resistance and response to new therapies. Mission Bio's multi-omics approach improves time-to-market for new therapeutics, including innovative cell and gene therapies that provide new pathways to health. Founded in 2014, Mission Bio has secured investment from Novo Growth, Cota Capital, Agilent Technologies, Mayfield Fund, and others.

The company's Tapestri platform gives researchers around the globe the power to interrogate every molecule in a cell together, providing a comprehensive understanding of activity from a single sample. Tapestri is the only commercialized multi-omics platform capable of analyzing DNA and protein simultaneously from the same sample at single-cell resolution. The Tapestri Platform is being utilized by customers at leading research centers, pharmaceutical, and diagnostics companies worldwide to develop treatments and eventually cures for cancer.

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