EXTH-38. AXL INHIBITION BY R428 ATTENUATES TEMOZOLOMIDE INDUCED pAXL EXPRESSION IN PATIENT DERIVED METASTATIC BRAIN CANCER CELLS
Year: 2017
Type: conference-abstract
Abstract: As patients with cancer are living longer, the incidence of brain metastasis is rising. Current treatment options for metastatic brain tumors are very limited. Axl, a receptor tyrosine kinase, has been reported as a key mediator for epithelial-mesenchymal transition (EMT), a process necessary for metastasis to occur. Increases of Axl expression have also been linked to highly aggressive and treatment resistance glioblastoma. A small molecule inhibitor of AXL (R428 – also known as BGB324) is currently in early phase clinical trials for non-small cell lung cancer and acute myeloid leukemia. Temozolomide (TMZ) is the standard chemotherapy of choice for primary brain tumors. We generated a patient derived cell line from a breast cancer metastasis to brain. The brain metastasis was (Her2, ER, PR negative). After confirming the cell line expressed Axl through Western blot and flow cytometry, we tested whether R428 alone or in combination with TMZ had any effect on Axl and pAxl expression. We also determined the impact of R428 and TMZ on cell proliferation. Interestingly, our data indicates a robust, inverse correlation between Axl and pAxl expression in response to TMZ treatment. As expected, R428 alone effectively inhibited the expression of pAxl and significantly attenuated TMZ mediated increases of pAxl expression in our patient-derived cell line. Additionally, our data suggests that increases in pAxl by TMZ may stimulate mechanisms that facilitate TMZ resistance. We will discuss the mechanisms and combination therapeutic effect on tumor growth during the meeting.
Source: Neuro-Oncology
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2767974244