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Abstract Lung adenocarcinomas (LUAD) are frequently driven by activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS). Previous studies have suggested that wild-type (wt) -RAS signaling may modulate cancer progression and drug resistance in these tumors. However, the interplay between oncogenic KRAS and wt-RAS-like GTPases in lung cancer biology and treatment remains debated. Here, we investigated the impact of increased wt-KRAS dosage in LUAD harboring mutant KRAS on lung cancer phenotypes and response to anti-KRAS therapies. Increased wt-KRAS dosage occurs in LUAD due to the loss of LZTR1, a proteostatic regulator of RAS-like GTPases. LZTR1 mutations, deletions, or downregulation co-occur with oncogenic KRAS mutations in more than 40% of LUAD patients. Using a global protein stability screen, we identified LZTR1 as the main regulator of the stability of wt-KRAS, but not of the oncogenic KRAS mutants. Proteomic analysis of LUAD cells confirmed that LZTR1 loss leads to elevated expression of wt-KRAS, but not of KRAS-G12D, indicating that LZTR1 loss affects wt-RAS rather than mutant KRAS signaling. LZTR1 loss in LUAD patients is associated with poor prognosis and hypoxic expression signatures. In a mouse model of Kras-mutated LUAD, Lztr1 haploinsufficiency promoted tumor initiation and progression. Moreover, Lztr1 loss results in hypoxic tumors with inflamed, tortuous, insufficiently perfused, and leaky vessels. Integrative proteomic and phosphoproteomic analysis revealed increased RAL/TBK1 pathway activity in LZTR1-depleted lung cancer cells and Lztr1-deleted tumors. This leads to enhanced secretion of proangiogenic and proinflammatory factors, such as VEGF and TNFα, by LZTR1-deficient cells and an increased number of neutrophils in Lztr1-deleted tumors. TNF-activated neutrophils present at vascular branching points can modulate vascular remodeling by influencing the formation and function of blood vessels. Pharmacological inhibition of RAL/TBK1 signaling with amlexanox, an anti-NF-κB/TBK1 drug, reduces TNFα secretion, decreases the number of neutrophils, and normalizes the tumor-associated vasculature. We demonstrated that increased wt-KRAS dosage, but not other small GTPases, mimicked the effects of LZTR1 loss on RAL/TBK1 signaling and VEGF secretion, suggesting that LZTR1 loss alters the heterogeneity of KRAS-mutated lung cancer by modulating wt-KRAS levels. Furthermore, MRTX1133 a selective inhibitor of KRAS-G12D, showed limited effect in the Kras-G12D, Lztr1-loss LUAD model, whereas the combination of MRTX1133 and amlexanox suppress tumor growth, likely due to the restoration of the tumor vasculature by RAL/TBK1 inhibition. Our study reveals novel insights into the role of wt-KRAS dosage in mutant KRAS lung cancer and identifies potential therapeutic strategies to target patients with dysregulated KRAS proteostasis due to LZTR1 loss. Citation Format: Tonci Ivanisevic, Greetje Vande Velde, Peihua Zhao, Wout Magits, Raj N. Sewduth, Anna A. Sablina. Wild-type KRAS dosage in mutant KRAS lung cancer: Implications for tumorigenesis and therapeutic response abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3941.
Ivanišević et al. (Fri,) studied this question.