AUTHOR=Kaehler Meike , Osteresch Pia , Künstner Axel , Vieth Stella Juliane , Esser Daniela , Möller Marius , Busch Hauke , Vater Inga , Spielmann Malte , Cascorbi Ingolf , Nagel Inga 

TITLE=Clonal evolution in tyrosine kinase inhibitor-resistance: lessons from in vitro-models

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1200897

DOI=10.3389/fonc.2023.1200897

ISSN=2234-943X

ABSTRACT=<sec><title>Introduction</title><p>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.</p></sec><sec><title>Methods</title><p>Here, we established an <italic>in vitro</italic>-TKI resistance model against the TKIs imatinib and nilotinib and performed exome sequencing.</p></sec><sec><title>Results</title><p>In this model, acquired sequence variants in <italic>NRAS</italic>, <italic>KRAS</italic>, <italic>PTPN11</italic>, and <italic>PDGFRB</italic> were identified in TKI resistance. The well-known pathogenic <italic>NRAS</italic> p.(Gln61Lys) variant provided a strong benefit for CML cells under TKI exposure visible by increased cell number (6.2-fold, p &lt; 0.001) and decreased apoptosis (-25%, p &lt; 0.001), proving the functionality of our approach. The transfection of <italic>PTPN11</italic> p.(Tyr279Cys) led to increased cell number (1.7-fold, p = 0.03) and proliferation (2.0-fold, p &lt; 0.001) under imatinib treatment.</p></sec><sec><title>Discussion</title><p>Our data demonstrate that our <italic>in vitro</italic>-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.</p></sec>