Investigating the reason for loss-of-function of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) caused by Y279C mutation through molecular dynamics simulation

Liu, Wen-Shan; Wang, Ruirui; Li, Weiya; Rong, Mingzhe; Liu, Chi-Lu; Ma, Ying; Wang, Run‐Ling

doi:10.1080/07391102.2019.1634641

Cited by 3 publications

(2 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a study in K-562 cells, it was shown that PTPN11 phosphorylation is induced during imatinib exposure as well as resistance and PTPN11 inhibition is able to restore TKI response ( 42 ). However, for p.(Tyr279Cys) in Leopard syndrome, a loss of catalytic activity was demonstrated ( 26 , 43 ). It is likely that the observed variant in PTPN11 results in an alteration of the phosphatase activity, which contributes to the development of TKI resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Further, it was demonstrated that PTPN11 is necessary for BCR:: ABL1-induced hematologic neoplasms, as its deletion compromised induction of CML in mice (41). In a study in K-562 cells, it was shown that PTPN11 phosphorylation is induced during imatinib exposure as well as resistance and PTPN11 inhibition is able to restore TKI response (42). However, for p.(Tyr279Cys) in Leopard syndrome, a loss of catalytic activity was demonstrated (26,43).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Kaehler,

Osteresch,

Künstner

et al. 2023

Front. Oncol.

View full text Add to dashboard Cite

IntroductionResistance 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.MethodsHere, we established an in vitro-TKI resistance model against the TKIs imatinib and nilotinib and performed exome sequencing.ResultsIn 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.DiscussionOur 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.

show abstract

Section: Discussionmentioning

confidence: 99%