Predicting the efficacy of BH3 mimetics through the profiling of multiple protein complexes

Chun, C.; Byun, J. M.; Cha, M.; Lee, H.; Choi, B.; Kim, H.; Hong, S.; Lee, Y.; Park, H.; Koh, Y.; Yoon, T.-Y.

doi:10.1101/2023.01.16.524337

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bioRxiv · 10.1101/2023.01.16.524337

Predicting the efficacy of BH3 mimetics through the profiling of multiple protein complexes

Chun, C.·Byun, J. M.·Cha, M.·Lee, H.·Choi, B.·Kim, H.·Hong, S.·Lee, Y.·Park, H.·Koh, Y.·Yoon, T.-Y.

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Abstract

BH3 mimetics are protein-protein interaction (PPI) inhibitors that saturate anti-apoptotic proteins in the BCL2 family to induce apoptosis in cancer cells, a prominent example of protein complex-targeting therapies. Despite the remarkable success of the BH3 mimetic ABT-199 in treating hematological malignancies, only a fraction of patients respond to ABT-199 and eventually develop resistance, necessitating the predictive biomarkers for both initial responses and resistance development. We here used the single-molecule pull-down and co-immunoprecipitation platform to quantify more than 20 different types of PPI complexes using [~]1.2x106 cells in total, revealing the rewired status of the BCL2 family PPI network. By comparing the obtained multi-dimensional data with BH3 mimetic efficacies determined ex vivo, we constructed an analysis model for ABT-199 efficacy that designates the BCL2-BAX and BCLxL-BAK complexes as the primary mediators of drug effectiveness and resistance. We then applied this model to assist in therapeutic decision-making for acute myeloid leukemia patients in a prospective manner. Our work demonstrates a capability for the extensive characterization of PPI complexes in clinical specimens, potentially opening a new avenue of precision medicine for protein complex-targeting therapies.

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Chun, C., Byun, J. M., Cha, M., Lee, H., Choi, B., Kim, H., Hong, S., Lee, Y., Park, H., Koh, Y., Yoon, T.-Y.. 2023-01-17. Predicting the efficacy of BH3 mimetics through the profiling of multiple protein complexes. https://doi.org/10.1101/2023.01.16.524337

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