Effective drugs are needed for
lung cancer, as this disease remains the leading cause of
cancer-related deaths. Rexinoids are promising drug candidates for
cancer therapy because of their ability to modulate genes involved in
inflammation, cell proliferation or differentiation, and apoptosis through activation of the
retinoid X receptor (RXR). The only currently FDA-approved rexinoid,
bexarotene, is ineffective as a single agent for treating epithelial
cancers and induces
hypertriglyceridemia. Here, we used a previously validated screening paradigm to evaluate 23 novel rexinoids for
biomarkers related to efficacy and safety. These
biomarkers include suppression of
inducible nitric oxide synthase (iNOS) and induction of
sterol regulatory element-binding protein (SREBP). Because of its potent iNOS suppression, low SREBP induction, and activation of RXR, MSU-42011 was selected as our lead compound. We next used MSU-42011 to treat established
tumors in a clinically relevant Kras-driven mouse model of
lung cancer. KRAS is one of the most common driver mutations in human
lung cancer and correlates with aggressive
disease progression and poor patient prognosis. Ultrasound imaging was used to detect and monitor
tumor development and growth over time in the lungs of the A/J mice. MSU-42011 markedly decreased the
tumor number, size, and histopathology of lung
tumors compared to the control and
bexarotene groups. Histological sections of lung
tumors in mice treated with MSU-42011 exhibited reduced cell density and fewer actively proliferating cells compared to the control and
bexarotene-treated
tumors. Although
bexarotene significantly (p < 0.01) elevated plasma
triglycerides and
cholesterol, treatment with MSU-42011 did not increase these
biomarkers, demonstrating a more favorable toxicity profile in vivo. The combination of MSU-42011 and
carboplatin and
paclitaxel reduced macrophages in the lung and increased activation markers of CD8+T cells compared to the control groups. Our results validate our screening paradigm for in vitro testing of novel rexinoids and demonstrate the potential for MSU-42011 to be developed for the treatment of KRAS-driven
lung cancer.