Abstract C108: Enhanced growth inhibition in lung cancer cells through NBF-006 combination therapy with chemotherapy or KRAS inhibitors

Abstract

Abstract Background: Glutathione-S-transferase P (GSTP) is strongly up-regulated in many cancer types, specifically KRAS-mutant lung and is also a known regulator of oncogenic MAPK and PI3K pathways. In cancer cells, overexpression of GSTP regulates apoptosis by inhibiting Jun-p53 complex in JNK pathway. NBF-006 is a novel lyophilized lipid nanoparticle formulation, encapsulating a small interfering ribonucleic acid (siRNA) designed to inhibit the expression of GSTP in lung tumors. NBF-006 has been very well tolerated with early signs of efficacy in NSCLC patients in a phase 1 dose escalation and expansion study. As NBF-006 is well tolerated and unlikely to have drug-drug interactions, combination strategies are currently being developed. Due to the detoxifying role of GSTP, combination with chemo agents used to treat NSCLC may increase the sensitivity of cancer cells resulting in apoptosis and/or reduced resistance. As GSTP and KRAS enhance tumor growth and survival, inhibition of GSTP and KRAS may be synergistic. Methods: Anti-tumor activity of GSTP siRNA (NDT-05-1040), when combined with chemo agents, KRAS inhibitors or immune cells was assessed in a panel of KRAS mutant NSCLC lines. For chemo agents and KRAS inhibitors, NDT-05-1040 combinations was evaluated using Combenefit software and Loewe model. Results: Combination of NDT-05-1040 with chemotherapy drugs including paclitaxel, gemcitabine, cisplatin, and pemetrexed controlled tumor cell growth significantly better than either NBF-006 alone or the chemo treatment alone. In A549, H1373, H358, and H1792 lines, at low doses paclitaxel combined with NDT-05-1040 and resulted in synergistic cell killing (Loewe scores >20). Gemcitabine & Cisplatin combination with NDT-05-1040 in H1373 cells further improved cell killing by 5-fold (Loewe scores >20). Pemetrexed combined with NDT-05-1040 and led to additive cell killing in A549 (Loewe score >10). Combination of NDT-05-1040 with KRASG12C inhibitors, Sotorasib & Adagrasib were conducted in H358, H1222, and MiaPaca-2. Cell viability assays demonstrated that the combination resulted in strong synergistic, anti-proliferative effects at low doses in H358 cells (the greatest Loewe scores for Adagrasib and Sotorasib: 53 & 26, respectively). Conclusion: Results from the current studies suggest that NBF-006, a very well tolerated monotherapy, can be used in combination with other drugs currently indicated for KRAS-mutant NSCLC to achieve more potent antitumor effects. Citation Format: Cima Cina, Akinori Sugiyama, Murali Kuracha, Nazia Abbasi, Dominic Medina, Hiroyuki Tanaka, Sonya Zabludoff. Enhanced growth inhibition in lung cancer cells through NBF-006 combination therapy with chemotherapy or KRAS inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C108.