LAUSR

Duvelisib is an oral, dual PI3K-δ,γ inhibitor that is FDA-approved for treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and follicular lymphoma (FL) following ≥2 prior systemic therapies. In addition to targeting malignant B cells, duvelisib regulates key non-malignant immune cells in the tumor microenvironment (TME), including Tregs and immunosuppressive myeloid cells. However, direct effects of duvelisib on solid tumor cells have not been tested. Here, we used the GEPIA webserver to analyze the expression of PIK3CD [PI3K-δ] and PIK3CG [PI3K-γ] from the TCGA database. Whereas PIK3CG was highly expressed in hematological malignancies (log2 median transcript per million, TPM+1 > 2) but not in solid tumors, PIK3CD was highly expressed in hematological malignancies (log2TPM+1 = 5.1 in DLBCL) as well as in a number of solid tumors, including melanoma (log2TPM+1 = 4.4) and head and neck squamous cell carcinoma (HNSCC) (log2TPM+1 = 3.2). Further, PIK3CD was more highly expressed in melanoma and HNSCC human tumor samples compared to adjacent normal tissue, suggesting a potential tumorigenic role of PI3K-δ. We also checked the expression of PIK3CD in human tumor cell lines from the Cancer Cell Line Encyclopedia database and found that 57% and 22% of the melanoma and HNSCC cell lines, respectively, expressed high levels (log2TPM+1 > 2) of PIK3CD, while 7% of melanoma cell lines expressed high levels of PIK3CG. To assess possible direct effects of duvelisib on solid tumor cells, the growth inhibitory activity of duvelisib was evaluated across 7 melanoma and 3 HNSCC cell lines expressing high levels of PI3K-δ and/or PI3K-γ. Cell viability was measured after 72-hour treatment with duvelisib (0.5nM-10μM) and reported as growth inhibition (GI) at 1μM. Duvelisib showed strong anti-proliferative activity (50-100% GI) in 3 out of 7 melanoma cell lines and 1 out of 3 HNSCC cell lines, and moderate activity (15-50% GI) in 3 melanoma cell lines and an additional HNSCC cell line. Duvelisib inhibited PI3K pathway activity, as measured by p-AKT and c-myc, in all the cell lines in which strong anti-proliferative activity was observed. Taken together, these findings indicate that in addition to the established effects of duvelisib on malignant B cells and non-malignant immune cells of the TME, duvelisib can also directly inhibit signaling and proliferation of solid tumor cells expressing PI3K-δ and/or PI3K-γ, providing further rationale for clinical investigation of duvelisib for the treatment of solid tumors. Accordingly, the combination of duvelisib with pembrolizumab is currently being evaluated in patients with head and neck squamous cell carcinoma. Citation Format: SILVIA COMA, David T. Weaver, Jonathan A. Pachter. The dual PI3K-δ/PI3K-γ inhibitor duvelisib inhibits signaling and proliferation of solid tumor cells expressing PI3K-δ and/or PI3K-γ [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 663.