2021 EORTC: Treatment with the dual mechanism ERK inhibitor, ASTX029, alters myeloid cell differentiation

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Treatment with the dual mechanism ERK inhibitor, ASTX029, alters myeloid cell differentiation


The inhibition of aberrant MAPK pathway activity is a clinically validated approach which has resulted in the approval of agents targeting tumors driven by activating mutations in BRAF and KRAS. Although the overall response rate to MAPK-targeting agents is high, duration of response is often limited by the emergence of acquired resistance. In contrast, immune checkpoint inhibitors (ICI) such as the anti-PD1 therapy, pembrolizumab, have a lower response rate but induce more durable responses. It has been demonstrated that inhibition of aberrant MAPK pathway activity enhances immune activation. For example, preclinical studies show that treatment with the BRAFV600E inhibitor dabrafenib or the KRASG12C inhibitor sotorasib induces a pro-inflammatory tumor microenvironment (TME), which is associated with increased anti-tumor immunity. Further, studies using syngeneic, MAPK-activated in vivo models have demonstrated that the combination of MAPK-targeting agents and ICI results in synergistic inhibition of tumor growth.

ASTX029 is a dual-mechanism ERK1/2 (ERK) inhibitor, inhibiting both the catalytic activity and phosphorylation of ERK, which is currently undergoing clinical development as part of a Phase 1/2 trial in advanced solid tumors (NCT03520075). ASTX029 has good oral bioavailability and shows potent inhibition of tumor growth in preclinical models bearing activating mutations in the MAPK pathway.

We have previously investigated the immunomodulatory effects of ASTX029 using an in vivo syngeneic tumor model and observed that treatment with ASTX029 resulted in a pro-inflammatory TME, with increased interferon signaling consistent with published data describing the effects of treatment with dual-mechanism ERK inhibitors (Kidger et al., Mol Cancer Ther, 2020). We also observed an increased expression of antigen presentation genes. Using digital spatial profiling, we evaluated the expression of 31 proteins in immune infiltrates and observed a significant decrease in CD14 and a significant increase in MHC class II in ASTX029-treated tumors compared to untreated tumors. We therefore investigated the immunomodulatory effects of ASTX029 using primary human monocytes under conditions that induce macrophage differentiation and polarisation. Treatment with ASTX029 induced a decrease in CD14 and an increase in MHC class II cell surface expression, consistent with our previous in vivo mouse model data. In addition, we observed changes in cell surface expression of phenotypic markers, such as CD206, following treatment with ASTX029.

These data support our previous observations and demonstrate that ERK inhibition by ASTX029 leads to phenotypic changes during monocyte to macrophage differentiation. Our data provide a strong rationale for the combination of ASTX029 with agents which aim to modulate the myeloid compartment or response to myeloid signaling.