AGO2 promotes tumor progression in KRAS-driven mouse models of non-small cell lung cancer.

Lung cancer is the deadliest malignancy in the United States. Non-small cell lung cancer (NSCLC) accounts for 85% of cases and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g., <i>KRASG12D</i>). Our previous work demonstrated that Argonaute 2 (AGO2)-a component of the RNA-induced silencing complex (RISC)-physically interacts with RAS and promotes its downstream signaling. We therefore hypothesized that AGO2 could promote <i>KRASG12D</i>-dependent NSCLC in vivo. To test the hypothesis, we evaluated the impact of <i>Ago2</i> knockout in the <i>KPC</i> (<i>LSL-Kras</i> <sup><i>G12D/+</i></sup> <i>;p53</i> <sup><i>f/f</i></sup> <i>;Cre</i>) mouse model of NSCLC. In KPC mice, intratracheal delivery of adenoviral Cre drives lung-specific expression of a stop-floxed <i>KRASG12D</i> allele and biallelic ablation of <i>p53</i> Simultaneous biallelic ablation of floxed <i>Ago2</i> inhibited KPC lung nodule growth while reducing proliferative index and improving pathological grade. We next applied the <i>KP</i> <sup><i>Het</i></sup> <i>C</i> model, in which the Clara cell-specific <i>CCSP</i>-driven Cre activates <i>KRASG12D</i> and ablates a single <i>p53</i> allele. In these mice, <i>Ago2</i> ablation also reduced tumor size and grade. In both models, <i>Ago2</i> knockout inhibited ERK phosphorylation (pERK) in tumor cells, indicating impaired KRAS signaling. RNA sequencing (RNA-seq) of <i>KPC</i> nodules and nodule-derived organoids demonstrated impaired canonical KRAS signaling with <i>Ago2</i> ablation. Strikingly, accumulation of pERK in KPC organoids depended on physical interaction of AGO2 and KRAS. Taken together, our data demonstrate a pathogenic role for AGO2 in KRAS-dependent NSCLC. Given the prevalence of this malignancy and current difficulties in therapeutically targeting KRAS signaling, our work may have future translational relevance.

Cao X, Cheng Y, Chinnaiyan AM, Chugh S, Dommeti VL, Goodrum AE, Hon J, Kenum C, Mannan R, Shankar S, Su F, Tien JC, Wang L, Wang R, Wang X, Xu A, Zhang Y

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Proc Natl Acad Sci U S A, 2021, 118 (20)

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