RB constrains lineage fidelity and multiple stages of tumour progression and metastasis

Abstract

Mutations in the Retinoblastoma (RB) tumour suppressor pathway are a hallmark of cancer and a prevalent feature of lung adenocarcinoma 1 , 2 , 3 . Despite being the first tumour suppressor to be identified, the molecular and cellular basis underlying selection for persistent RB loss in cancer remains unclear 4 – 6 . Methods that reactivate the RB pathway using inhibitors of cyclin-dependent kinases CDK4 and CDK6 are effective in some cancer types and currently under evaluation in lung adenocarcinoma 7 – 9 . Whether RB pathway reactivation will have therapeutic effects and if targeting CDK4/6 is sufficient to reactivate RB pathway activity in lung cancer is unknown. Here, we model RB loss during lung adenocarcinoma progression and pathway reactivation in established oncogenic KRAS-driven tumours in the mouse. We show that RB loss enables cancer cells to bypass two distinct barriers during tumour progression. First, RB loss abrogates the requirement for MAPK signal amplification during malignant progression. We identify CDK2-dependent phosphorylation of RB as an effector of MAPK signalling and critical mediator of resistance to CDK4/6 inhibition. Second, RB inactivation deregulates expression of cell state-determining factors, facilitates lineage infidelity, and accelerates the acquisition of metastatic competency. In contrast, reactivation of RB reprograms advanced tumours toward a less metastatic cell state, but is nevertheless unable to halt cancer cell proliferation and tumour growth due to adaptive rewiring of MAPK pathway signalling, which restores a CDK-dependent suppression of RB. Our study demonstrates the power of reversible gene perturbation approaches to identify molecular mechanisms of tumour progression, causal relationships between genes and the tumour suppressive programs they control, and critical determinants of successful therapy.

Impaired AKT signaling and lung tumorigenesis by PIERCE1 ablation in KRAS-mutant non-small cell lung cancer

“…The cancer promoting activity and lung-specific expression of PIERCE1 prompted us to examine the link between PIERCE1 and lung cancer. Moreover, ablation of RB, one of the major suppressors of PIERCE1 expression, accelerates tumor progression in lung adenocarcinoma [26], potentiating our hypothesis. We first analyzed overall and progression-free survival rates of total lung cancer cases from the Kaplan-Meier plotter [27].…”

Tumor Milieu Controlled by RB Tumor Suppressor

“…It has been reported that RB promotes differentiation that is independent of the cell cycle regulation and RB-inactivated cells, therefore, exhibit defective terminal differentiation [1][2][3]. Interestingly, aberration of the RB gene often correlates with appearance of phenotypes associated with dedifferentiation or transdifferentiation in lung cancer, prostate cancer, and breast cancer [27][28][29][30][31]. The lineage plasticity induced by RB inactivation would promote the resistance to therapies by epidermal growth factor receptor (EGFR) inhibitors, estrogen and androgen receptor antagonists, and androgen deprivation (castration) because these treatments generally target cell lineage-specific characteristics of tumors [28,29,[32][33][34].…”

Sox2-dependent maintenance of mouse oligodendroglioma involves the Sox2-mediated downregulation of Cdkn2b, Ebf1, Zfp423 and Hey2

“…This finding, together with observations by several authors, points to the possibility of identifying proteins which are "druggable" and thus allowing to slow down tumor progression. In this regard, a recent paper (Rubin & Sage, 2019;Walter et al, 2019) showed that mutating the Cdk2 gene in lung adenocarcinoma tumor cells sensitized these cells to the action of palbociclib, an inhibitor of Cdk4/6 kinases (themselves repressed by CDKN2b), which are frequently activated in these tumors. Our observation that Sox2 inhibits several genes which act as antioncogenes points to the exciting possibility of developing drugs able to prevent the ability of Sox2 (or interacting proteins, such as Groucho) to repress these genes.…”