Strich 2023 MiPschool Obergurgl

Bioenergetic profiling of kinase inhibitors reveals drug off-targer effects in colon cancer cell models

Link: MiPschool Obergurgl 2023

Strich Sophie (2023)

Event: MiPschool Obergurgl 2023

Authors: Omar Torres-Quesada , Sophie Strich , Andreas Feichtner , Selina Schwaighofer , Carolina Doerrier, Sabine Schmitt, Erich Gnaiger, Eduard Stefan

Protein kinases play an important role in numerous signaling pathways regulating cell proliferation, cell cycle, and metabolism. Deregulation of kinase functions have been connected to various human diseases, such as cancer [1]. In recent years, kinase inhibitors have gained recognition by aiming to block single or multiple oncogenic kinase pathways [2]. In these lines, blockade of kinase activities has been shown to converge on the central energetic organelle, the mitochondria [3, 4]. Furthermore, colon cancer cells rely on mitochondrial OXPHOS as major source of energy, contradicting the Warburg effect [5].
To increase the understanding of small molecule-based kinase blockers and their cell-type-specific adverse effects, we set out to record the impact of kinase drugs on mitochondrial respiration using High-resolution FluoRespirometry in several colon cancer cell models. We observed that the impact of kinase inhibitors depends on the mutational background of the tested cancer cell lines as well as on cell culture medium formulations [6]. First, we detected off-target effects of sunitinib, an FDA-approved multikinase blocker, only in a more physiological cell culture medium as compared with classical formulations. Second, mitochondrial profiling of the glycolytic kinase inhibitor PFK158 revealed off-target mitochondrial dysfunction. Third, we were able to show that inhibition of kinase signaling is connected to mitochondrial reactive oxygen species (ROS), which can be influenced by protein kinase modulators. In summary, cell-based mitochondrial bioenergetic profiles have the power to identify off-target effects of kinase inhibitors and allow a detailed mechanistic insight on drug-induced perturbations in cancer cell metabolism.

1. Cohen, P, Cross, D, Jänne, PA (2021). Kinase drug discovery 20 years after imatinib: progress and future directions. Nat Rev Drug Discov. 20(7):551-569. https://doi.org/10.1038/s41573-021-00195-4
2. Zhang J, Yang PL, Gray NS (2009). Targeting cancer with small molecule kinase inhibitors. https://doi.org/10.1038/nrc2559
3. Wallace, DC (2012). Mitochondria and Cancer Nat. Rev. Cancer, 12, 685–698. https://doi.org/10.1038/nrc3365
4. Torres-Quesada O, Strich S, Stefan E (2022). Kinase perturbations redirect mitochondrial function in cancer. Bioenerg. Commun. 2022,13. https://doi.org/10.26124/bec:2022-0013
5. Sun, X., Zhan, L., Chen, Y. et al. (2018) Increased mtDNA copy number promotes cancer progression by enhancing mitochondrial oxidative phosphorylation in microsatellite-stable colorectal cancer. Sig Transduct Target Ther 3, 8. https://doi.org/10.1038/s41392-018-0011-z
6. Torres-Quesada, O, Doerrier, C, Strich, S, Gnaiger, E, Stefan, E (2022). Physiological Cell Culture Media Tune Mitochondrial Bioenergetics and Drug Sensitivity in Cancer Cell Models. Cancers, 14, 3917. https://doi.org/10.3390/cancers14163917

• Keywords: kinase signaling, mitochondria, kinase inhibitors, cancer, drug off-target effects

• O2k-Network Lab: AT Innsbruck Oroboros

Labels: Pathology: Cancer 

HRR: Oxygraph-2k, O2k-Fluorometer  Event: E2