Exome sequencing identifies PTPN11, PDGFRB, KRAS, and NRAS mutations in TKI resistance

Resistance in anti-cancer treatment is a result of clonal evolution and clonal selection. In chronic myeloid leukemia (CML), a hematopoietic neoplasm predominantly caused by the formation of the BCR-ABL1 kinase, treatment with tyrosine kinase inhibitors (TKIs) is tremendously successful. It has become the role model of targeted therapy. However, therapy resistance leads to loss of molecular remission in about 25 percent of CML patients. Resistance against TKIs is partially due to BCR-ABL1 kinase mutations, while for the remaining cases, various mechanisms are discussed. Here, we established an in vitro-TKI resistance model against the TKIs imatinib and nilotinib and performed exome sequencing. In our model, acquired sequence variants in NRAS, KRAS, PTPN11, and PDGFRB were identified in TKI resistance.