Researchers identify BTK inhibitor-resistant clones with Mission Bio

By The Science Advisory Board staff writers

February 28, 2022 -- Mission Bio, in conjunction with researchers at Memorial Sloan Kettering Cancer Center and the University of Miami, has published new findings 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 published in the New England Journal of Medicine, researchers 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). 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.

The authors confirmed some patients developed resistance to pirtobrutinib, with disease progression seen in 9 of 55 patients with CLL. They 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.

These studies revealed that both primary (pre-existing) and secondary (acquired) resistance mechanisms were present. 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.

If patients can be 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, according to the company.

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