Dr.
Combination of olverembatinib (HQP1351) with Bcl-2 inhibitor lisaftoclax (APG-2575) overcomes resistance in gastrointestinal stromal tumors (GISTs)
Orebatinib (HQP1351) combined with Bcl-2 inhibitor APG-2575 can overcome drug resistance in gastrointestinal stromal tumors (GISTs)
Abstract number: 1631
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GIST is a common malignant stromal tumor of the digestive tract, and its incidence is about 1%-2%. About 75%-80% of GIST patients have KIT gene mutations, and about 5-10% have platelet-derived growth factor receptor alpha (PDGFRA) gene mutations. Although tyrosine kinase inhibitors (TKIs) can improve the quality of life of patients, TKI resistance also commonly occurs. More than 80% of GIST patients express Bcl-2, and the amplification of Bcl-2 and Bcl-xL may be a common feature associated with disease progression. Inhibiting oncogenic KIT signaling while acting on the apoptotic pathway is one of the therapeutic strategies for GIST. Orebatinib (HQP1351) is a new third-generation TKI that can target BCR-ABL1, KIT and PDGFRA, and is undergoing clinical trials for the treatment of relapsed/refractory chronic myeloid leukemia and GIST. APG-2575 is a selective Bcl-2 inhibitor in clinical trials for the treatment of hematological malignancies. This study aimed to evaluate whether the Bcl-2 inhibitor APG-2575 combined with orebatinib can improve the efficacy of imatinib-resistant GIST.
The results of this preclinical study showed that orebatinib and the Bcl-2 inhibitor APG-2575 have synergistic antitumor effects in imatinib-resistant GIST. Considering that most TKIs have similar resistance mechanisms, this new dual-drug combination therapy is expected to bring a new treatment strategy for GIST patients who develop resistance after receiving imatinib or other TKIs.
Olverembatinib (HQP1351) enhances antitumor effects of immunotherapy in renal cell carcinoma (RCC)
Orebatinib (HQP1351) enhances the antitumor effect of immunotherapy in renal cell carcinoma (RCC)
Abstract number: 5071
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Checkpoint inhibitor (CPI) resistance is common in many solid tumors. Reasons for this include upregulation of vascular endothelial growth factor A (VEGFA) and programmed death-ligand 1 (PD-L1), resulting in an immunosuppressive tumor microenvironment and immune escape. VEGF and VEGF receptor (VEGFR) inhibitors can promote the normalization of tumor blood vessels and the reprogramming of immunostimulatory cells, thereby enhancing the efficacy of immunotherapy. In recent years, several combinations of tyrosine kinase inhibitors (TKIs) and immunotherapy have been approved for the treatment of advanced RCC. Orebatinib is a new generation multi-kinase inhibitor that acts on VEGFR, fibroblast growth factor receptor (FGFR), SRC, BCR-ABL1, c-KIT and platelet-derived growth factor receptor multiple targets. The drug has been approved in
The results of this preclinical study showed that Orebatinib combined with CPI achieved a synergistic anti-tumor effect in a mouse model of renal cell carcinoma by targeting tumor growth, angiogenesis and immune regulation. This novel combination therapy is expected to provide a new strategy to enhance the efficacy of CPI for patients with RCC.
MDM2 inhibitor alrizomadlin (APG-115) promotes antitumor activity of mitogen-activated protein kinase (MAPK) inhibitors in uveal melanoma
MDM2 inhibitor APG-115 enhances the antitumor activity of mitogen-activated protein kinase (MAPK) inhibitors in uveal melanoma
Abstract number: 1632
Time:
Uveal melanoma (UM) is the most common primary intraocular malignancy, yet knowledge of the molecular pathogenesis of the disease remains very limited. Most patients with UM have mutations in the genes encoding the G-protein subunits Q or 11, which lead to protein kinase C, mitogen-activated protein kinase (also known as MAPK1/3 or extracellular signal-regulated kinase 2/1 [ERK2/ ERK1]) and activation of downstream effectors such as YES-related proteins. This provides a rationale for targeting these pathways in therapy. Genetic analysis revealed that TP53 mutations are rare in UM patients, but the pathways associated with it may be functionally inactive. Ubiquitination-mediated degradation of p53 activates MAPK signaling, so active p53 may enhance inhibition of MAPK signaling. APG-115 is a small molecule drug targeting p53/MDM2, which is undergoing clinical trials for the treatment of various solid tumors and blood tumors. The study aims to evaluate the anti-tumor activity of APG-115 alone and in combination with other targeted drugs in preclinical UM models.
The results of this preclinical study showed that APG-115 combined with MAPK pathway inhibitors has therapeutic potential for UM.
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