Reactivating RB via CDK2 Inhibition Reduces Lung Cancer Aggressiveness

Although inactivation of the retinoblastoma (RB) tumor suppressor is common in lung adenocarcinoma and is associated with poor patient survival, successful methods to reactivate RB signaling have yet to be determined. Activation of cyclin-dependent kinases 4 and 6 (CDK4/6) by RAS/MAPK signaling promotes progression through G1 through phosphorylation and inactivation of RB, suggesting that CDK4/6 inhibition may reactivate RB in lung adenocarcinoma. Walter, Yates, Ruiz-Torres, and colleagues modeled the effects of RB inactivation and reactivation in lung adenocarcinoma and determined that loss of RB in a KRAS-driven mouse model resulted in decreased differentiation, increased tumor grade, and increased metastatic load. Consistent with these observations, patients with lung adenocarcinomas that harbored RB pathway alterations were more likely to have higher-grade tumors and metastatic disease compared with patients with RB–wild-type tumors. Additionally, RB-deficient tumors and cell lines coexpressed the lineage-specific transcription factors NKX2-1 and FOXA2 and the metastasis-associated chromatin-regulator factor HMGA2, indicating that loss of RB disrupted lineage fidelity to promote metastatic ability. Of interest, this increased aggressiveness in the setting of mutant KRAS was not due to an increase in MAPK signaling as measured by the canonical effectors phospho-MEK and phospho-ERK. However, analysis of mouse and human lung adenocarcinoma specimens revealed a correlation between high RB phosphorylation, increased tumor grade, and high phosphorylation and inactivation of p27, a negative regulator of CDK2, suggesting a role for CDK2-mediated inhibition of RB. Indeed, inactivation of CDK2 via CRISPR reactivated RB and sensitized RB–wild-type human lung cancer cell lines to the CDK4/6 inhibitor palbociclib. Genetic reactivation of RB signaling significantly increased survival, reduced tumor growth and metastasis, decreased expression of HMGA2, and decreased coexpression of HMGA2 and NKX2-1. Together, these data suggest loss of RB plays an important role in reprogramming tumors to a more metastatic, less differentiated state. Activation of RB signaling via CDK2 inhibitors may provide a promising therapeutic option for patients with lung adenocarcinoma with RB pathway alterations.

Walter DM, Yates TJ, Ruiz-Torres M, Kim-Kiselak C, Gudiel AA, Deshpande C, et al. RB constrains lineage fidelity and multiple stages of tumour progression and metastasis. Nature 2019;569:423–7.

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