Ras inhibition by FTS attenuates brain tumor growth in mice directly and by enhancing reactivity of cytotoxic lymphocytes

Abstract

One of the concerns in targeted drug therapy is that the inhibition of receptors and signaling molecules in tumor cells may also affect similar components in the tumor microenvironment or in the immune system, with undefined consequences for inhibition of tumor growth. Thus, in addition to its antitumor activity in mice and humans, the Ras inhibitor salirasib (S-farnesylthiosalicylic acid, FTS) also exhibits anti-inflammatory activity. Here we show three antitumor effects of FTS in immune-competent mice with subcutaneous or intracranial tumors. First, FTS exhibited antitumor activity in immune-competent, intracranial tumor-bearing mice and increased their survival relative to tumor-bearing immune-compromised mice. Second, FTS induced an increase in regulatory T cells in mouse splenocytes, but the inhibitory effects of FTS on tumor growth were not affected by these Foxp3+ T lymphocytes. Third, FTS increased antitumor T-cell reactivity by downregulating Foxp3. This caused TGF-β-dependent sensitization of the tumor to the immune system.