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
PubMed ID
Appears In
Proc Natl Acad Sci U S A, 2021, 118 (20)