Abstract 4682: Influence of PI3K/AKT pathway on imatinib mesylate treatment outcome in chronic myeloid leukemia patients

Abstract

Abstract Chronic myeloid leukemia (CML) is a common myeloproliferative disorder characterized by cytogenetic abnormality [t(9;22)(q34;q11)] that generates BCR-ABL oncogene with aberrant tyrosine kinase activity, the driver event in CML origin. Tyrosine kinase inhibitors (TKIs) are remarkably effective; yet, treatment failure is common in some cases due to the accumulation of mutations in BCR-ABL itself and other genes causing drug resistance/relapse, which indicates that BCR-ABL inhibition alone may not be sufficient to combat CML. The PI3K/Akt/mTOR signaling pathway downstream of BCR-ABL has been proven to be an important survival mechanism in leukemias. In vitro studies demonstrated that targeting this pathway could be a viable strategy, but needs further validation in CML patients. In this study, we examined the critical PI3K/AKT/mTOR pathway genes (PIK3CA, PTEN, AKT1, SHIP1, mTOR, and FOXO3A) in CML patients (n=51) using qPCR method at diagnosis and after treatment, and analyzed with respect to BCR-ABL status, and JAK2, STAT5, and STAT3 levels. Interestingly, significant upregulation of AKT1 (p=0.012) and PIK3CA (p=0.026) and downregulation of PTEN (P=0.06) and SHIP1 (p=0.039) was observed in samples at diagnosis compared to their post imatinib treated. Remarkably, these elevated AKT1 and PI3KCA transcript levels were significantly associated with increased BCR-ABL and JAK2 transcript levels, but not STAT3 and STAT5 suggesting PI3K pathway as a prominent target in CML. However, with respect to the clinical phase and imatinib response, none of the genes showed significant differences except for PTEN, which was significantly downregulated in advanced phase (p<0.042) and in cases with poor imatinib response. Overall, these results indicate a critical role for PI3K pathway in CML and its maintenance. Citation Format: Swathi Banapuram, Manjula Gorre, Raghunadha Rao Digumarti, Vishnupriya Satti, Komaraiah Palle, Sandhya Annamaneni. Influence of PI3K/AKT pathway on imatinib mesylate treatment outcome in chronic myeloid leukemia patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4682.