Unravelling Resistance Mechanisms in Philadelphia Positive Leukemias: Targeted Treatment Strategies to Overcome Resistance
Date
2023
Authors
Poudel, Govinda
Editors
Advisors
Hughes, Timothy
Yeung, David
Pagani, Ilaria
Yeung, David
Pagani, Ilaria
Journal Title
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Thesis
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Abstract
The advent of Tyrosine Kinase Inhibitors (TKIs) has significantly improved the survival outcomes of Philadelphia-positive (Ph+) leukaemias, including Chronic Myeloid Leukaemia (CML) and Ph+ Acute Lymphoblastic Leukaemia (ALL). However, the development of TKI resistance remains a major challenge, particularly in cases where mutations other than in BCR::ABL1 are involved. Cancer-associated gene mutations, such as those in Protein tyrosine phosphatase non-receptor type-11 (PTPN11), are frequently found in patients with poor prognosis, but their role in mechanisms of resistance is poorly understood. In this study, I investigated the role of two PTP domain PTPN11 mutations (p.A461T and p.P491H) in cell line models of Ph+ ALL. I modelled these mutations in multiple cell lines and demonstrated that they directly lead to TKI resistance. I also showed that Ph+ ALL cell lines with PTPN11 mutations were resistant to venetoclax, a BCL-2 inhibitor. I found that genetically knocking down PTPN11 could sensitize cells to both TKIs and venetoclax. Furthermore, I demonstrated a novel mechanism of TKI resistance involving reactivation of pBCR-Y177 part of BCR::ABL1 and overexpression of pERK1/2 and antiapoptotic protein BCL-XL. This study is the first to show BCR::ABL1 dependent mechanisms of resistance driven by non-BCR::ABL1 mutations. I investigated potential therapeutic options and demonstrated that targeting the antiapoptotic proteins BCL-2 and MCL-1 could overcome resistance in Ph+ ALL cells with PTP domain PTPN11 mutations. Inhibition of MCL-1 in these cells could also be achieved by blocking BCR::ABL1 activation, which also overcame resistance when combined with venetoclax. This discovery of a new precision medicine approach could be a promising treatment option for Ph+ ALL patients carrying PTP domain PTPN11 mutations. I also investigated targeting MEK, an upstream molecule of ERK in MAPK pathway, with its inhibitor to overcome resistance, but its clinical translation may be limited due to its significant side effects. Before testing this combination treatment option for Ph+ ALL patients in clinical trials, future work should test this treatment option in mouse models. In conclusion, this study not only provides a promising treatment option for Ph+ ALL patients carrying PTPN11 mutations, but also adds knowledge in understanding the function of the poorly understood SHP-2 protein and implications when mutations are acquired in the PTP domain. The knowledge from this study could also be used in understanding the mechanisms of poor response and resistance in Ph- leukaemias such as JMML, AML and MDS where PTPN11 mutations are highly prevalent, and patients have very limited treatment options.
School/Discipline
Adelaide Medical School
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2023
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