Ferroptosis induction synergizes with KRAS inhibitors in KRAS-mutant lung adenocarcinoma
Presenter: Amirali Karimi, MD Session: Cell Death Pathways and Treatment Time: 4/21/2026 2:00:00 PM → 4/21/2026 5:00:00 PM
Authors
Amirali Karimi 1 , Yu Qian 1 , David Molkentine 1 , Alvaro Guimaraes Paula 1 , Busra Ernhofer 2 , David Hwa Peng 3 , Monique B. Nilsson 1 , John V. Heymach 1 1 Department of Thoracic, Head and Neck Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, 2 Medical University of Vienna, Vienna, Austria, 3 Therapeutics Discovery Division, TRACTION Platform, UT MD Anderson Cancer Center, Houston, TX
Abstract
Background : KRAS inhibitors hold substantial potential for the treatment of numerous malignancies harboring activating KRAS mutations, including non-small cell lung cancer (NSCLC). KRAS mutations are present in 25-30% of patients with non-squamous NSCLC, most commonly in the form of G12C mutations. Unfortunately, patients with inactivating mutations in KEAP1 , which is frequently co-mutated with KRAS and STK11 /LKB1 , respond poorly to KRAS G12C inhibitors. KEAP1 inactivation impairs NRF2 protein degradation, leading to enhanced antioxidant and ferroptosis response in the tumor cells. Whether ferroptosis resistance mediates resistance to KRAS G12C and G12D inhibitors in lung adenocarcinoma cells harboring these mutations is unknown. Methods : DepMap was used to retrieve the drug sensitivity data for RSL3, erastin, ML162, ML210, sotorasib, and MRTX1133 as well as CRISPR and RNAi screen data in NSCLC human cell lines. A NSCLC ferroptosis resistance gene signature was constructed using genes that positively correlated (Pearson correlation z-score > 3) with resistance to both RSL3 and erastin in human NSCLC cell lines accessed from the Cancer Therapeutics Response Portal. We knocked-out Keap1 and Stk11 from murine LKR13 KRAS G12D and KRAS G12C cells using CRISPR-Cas9, to create isogenic models of Kras MUT (K), Kras MUT / Keap1 KO (KK), Kras MUT / Lkb1 KO (KL), and Kras MUT / Lkb1 KO / Keap1 KO (KLK) tumor cells. Lipid peroxidation was quantified by flow cytometry using BODIPY™ 581/591 C11. Results : We determined that KEAP1 -mutant, but not LKB1-mutant, NSCLC cell lines were resistant to ferroptosis inducers RSL3, ML162, ML210, and erastin. KEAP1 deficiency also correlated with poor response to KRAS G12C inhibitors (sotorasib and adagrasib) and the KRAS G12D inhibitor MRTX1133 in human and murine cell lines, suggesting that ferroptosis resistance may contribute to KRAS inhibitor resistance. Treatment of KRAS mutant tumor cells with adagrasib or MRTX1133 induced lipid peroxidation- the biochemical defining feature of ferroptosis. In KRAS G12D mutant LKR13 cells, MRTX1133-induced cell death could be partially reversed by the ferroptosis inhibitor ferrostatin-1, but not by apoptosis or necroptosis inhibitors. Moreover, a higher NSCLC ferroptosis resistance gene expression signature correlated with reduced sensitivity to KRAS gene disruption in CRISPR and RNAi screens in KRAS -mutant NSCLC cell lines. Finally, ferroptosis inducers erastin and RSL3 synergized with adagrasib and MRTX1133 in LKR13 K cell lines. Conclusions : KRAS inhibition induces ferroptosis in KRAS -mutant lung adenocarcinoma cell lines and ferroptosis resistance correlates with resistance to KRAS inhibitors. Combining ferroptosis induction strategies could potentially enhance the effectiveness of KRAS targeting treatments.
Disclosure
A. Karimi, None.. Y. Qian, None.. D. Molkentine, None.. A. Guimaraes Paula, None.. B. Ernhofer, None.. D. H. Peng, None. M. B. Nilsson, Spectrum Pharmaceuticals Other, Royalties and licensing fees. J. V. Heymach, AstraZeneca ), Other, Advisory Committee. Taiho Pharmaceuticals ). Boehringer-Ingelheim Pharmaceuticals ), Other, Advisory Committee. Spectrum Pharmaceuticals ), Other, Advisory Committee, Licensing and Royalties. Mirati Therapeutics ), Other, Advisory Committee. Bristol-Myer Squibb ). Takeda Pharmaceuticals ), Other, Advisory Committee. Genentech Other, Advisory Committee. Eli Lilly & Co Other, Advisory Committee. Janssen Pharmaceuticals Other, Advisory Committee. Regeneron Other, Advisory Committee. BerGenBio Other, Advisory Committee. Jazz Pharmaceuticals Other, Advisory Committee. Curio Science Other, Advisory Committee. Novartis Other, Advisory Committee. BioAlta Other, Advisory Committee. Sanofi Other, Advisory Committee. GlaxoSmithKline, EMD Serono, BluePrint Medicine, Chugai Pharmaceutical Other, Advisory Committee. Clinical Care Targeted Communications, Physicians Education Resource (PER), Prime Education Other, Speaking Events. Tenaci-T Therapeutics Other, Business Ownership.
Cited in
Control: 7898 · Presentation Id: 4607 · Meeting 21436