Abstract
Introduction: Resistance in anti-cancer treatment is a result of clonal evolution and clonal selection. In chronic myeloid leukemia (CML), the hematopoietic neoplasm is predominantly caused by the formation of the BCR::ABL1 kinase. Evidently, treatment with tyrosine kinase inhibitors (TKIs) is tremendously successful. It has become the role model of targeted therapy. However, therapy resistance to TKIs leads to loss of molecular remission in about 25% of CML patients being partially due to BCR::ABL1 kinase mutations, while for the remaining cases, various other mechanisms are discussed. Methods: Here, we established an in vitro-TKI resistance model against the TKIs imatinib and nilotinib and performed exome sequencing. Results: In this model, acquired sequence variants in NRAS, KRAS, PTPN11, and PDGFRB were identified in TKI resistance. The well-known pathogenic NRAS p.(Gln61Lys) variant provided a strong benefit for CML cells under TKI exposure visible by increased cell number (6.2-fold, p < 0.001) and decreased apoptosis (-25%, p < 0.001), proving the functionality of our approach. The transfection of PTPN11 p.(Tyr279Cys) led to increased cell number (1.7-fold, p = 0.03) and proliferation (2.0-fold, p < 0.001) under imatinib treatment. Discussion: Our data demonstrate that our in vitro-model can be used to study the effect of specific variants on TKI resistance and to identify new driver mutations and genes playing a role in TKI resistance. The established pipeline can be used to study candidates acquired in TKI-resistant patients, thereby providing new options for the development of new therapy strategies to overcome resistance.
| Original language | English |
|---|---|
| Article number | 1200897 |
| Journal | Frontiers in Oncology |
| Volume | 13 |
| Pages (from-to) | 1200897 |
| ISSN | 2234-943X |
| DOIs | |
| Publication status | Published - 2023 |
Funding
We thank Irina Naujoks, Anna Jürgensen and Britta Schwarten for outstanding technical assistance. We thank the Institute of Clinical Molecular Biology in Kiel for providing Sanger sequencing, as partly supported by the DFG Clusters of Excellence “Precision Medicine in Chronic Inflammation” and “ROOTS”. We thank Claudia Becher from the Institute of Human Genetics in Kiel for her technical assistance. AK thanks the computational support from the OMICS compute cluster at the University of Lübeck. This study was funded by a grant from the Medical Faculty of the University of Kiel. HB acknowledges funding by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC22167-390884018. Acknowledgments
Research Areas and Centers
- Research Area: Medical Genetics
DFG Research Classification Scheme
- 2.22-03 Human Genetics
