Inhibition of stearoyl-CoA desaturase 1 (SCD1) by SSI-4 as a therapeutic strategy in non-small cell lung cancer

Lipid metabolism plays an important role in lung cancer growth, survival, and therapeutic resistance. Stearoyl-CoA desaturase 1 (SCD1), the enzyme that converts saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs), represents a metabolic vulnerability since cancer cells depend on MUFAs for membrane biosynthesis, ER homeostasis, and alternative energy to glucose. SSI-4 (a.k.a MTI-301) is a selective SCD1 inhibitor currently in Phase I clinical evaluation for metastatic, unresectable, or refractory solid cancers, but its activity in non-small cell lung cancer (NSCLC) has not yet been characterized. To evaluate how NSCLC models respond to SCD1 blockade, we performed an initial screen of a panel of 17 human non-small cell lung cancer cell lines treated with 100 nM SSI-4 under defined serum conditions. Cell viability assays identified 9 responding cell lines, and dose-response studies confirmed IC50 values ranging from approximately 0.65 to 45.5 nM. Rescue experiments showed that adding oleic acid, an SCD1 regulated MUFA, reversed SSI-4-mediated growth inhibition, confirming mechanistically that this effect occurs through SCD1 blockade. Western blot analysis confirmed that SSI-4 treatment increased markers of endoplasmic reticulum (ER) stress and apoptosis in sensitive lines, consistent with disruption of lipid homeostasis. In contrast, non-responsive lines exhibited minimal induction of these stress pathways and retained viability despite treatment. Soft agar assays further showed that SSI-4 reduced anchorage-independent colony formation in responsive lines, indicating that SCD1 inhibition suppresses a key malignant growth property in these NSCLC models. Collectively, these findings demonstrate that SSI-4 selectively inhibits proliferation in a subset of NSCLC cells through an SCD1-dependent mechanism by reducing MUFA availability and activating stress and apoptotic signaling. This work establishes a framework for subsequent in vivo studies and lays the foundation for exploring SCD1 inhibition as a potential therapeutic strategy for patients with limited treatment options in NSCLC, while also advancing understanding of the mechanisms by which SCD1 supports tumor survival.