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

• Published in: Nature (London) Vol. 569; no. 7756; pp. 423 - 427
• Main Authors: Walter, David M., Yates, Travis J., Ruiz-Torres, Miguel, Kim-Kiselak, Caroline, Gudiel, A. Andrea, Deshpande, Charuhas, Wang, Walter Z., Cicchini, Michelle, Stokes, Kate L., Tobias, John W., Buza, Elizabeth, Feldser, David M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2019; Nature Publishing Group
• Subjects: 13/1; 13/105; 13/106; 13/109; 13/31; 13/44; 13/51; 14/1; 14/35; 14/63; 38/22; 38/39; 38/77; 38/90; 38/91; 3T3 Cells; 42/109; 42/41; 45; 45/29; 45/90; 45/91; 59/57; 631/67/1244; 631/67/1612/1350; 631/67/70; 64/110; 64/60; 82/1; 82/51; 82/80; Activation; Adenocarcinoma; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Analysis; Animals; Cancer; Cancer therapies; Cell growth; Cell Lineage - genetics; Cell proliferation; CRISPR; Cyclin-dependent kinase 2; Cyclin-Dependent Kinase 2 - deficiency; Cyclin-Dependent Kinase 2 - genetics; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-dependent kinases; Deactivation; Deregulation; Development and progression; Disease Progression; Fidelity; Genetic aspects; Genomes; Genomics; HEK293 Cells; Humanities and Social Sciences; Humans; Identification and classification; Inactivation; Kinases; Letter; Lung cancer; Lung diseases; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; MAP kinase; MAP Kinase Signaling System; Metastases; Metastasis; Mice; Molecular modelling; multidisciplinary; Mutation; Neoplasm Metastasis - genetics; Phosphorylation; Retina; Retinoblastoma; Retinoblastoma - genetics; Retinoblastoma - metabolism; Rewiring; Science; Science (multidisciplinary); Signal transduction; Signaling; Tumor suppressor genes; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1172-9

Mutations in the retinoblastoma (RB) tumour suppressor pathway are a hallmark of cancer and a prevalent feature of lung adenocarcinoma 1 – 3 . Although RB was the first tumour suppressor to be identified, the molecular and cellular basis that underlies 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 are currently under evaluation for the treatment of lung adenocarcinoma 7 – 9 . Whether RB pathway reactivation will have therapeutic effects and whether targeting CDK4 and CDK6 is sufficient to reactivate RB pathway activity in lung cancer remains unknown. Here we model RB loss during lung adenocarcinoma progression and pathway reactivation in established oncogenic KRAS-driven tumours in mice. We show that RB loss enables cancer cells to bypass two distinct barriers during tumour progression. First, RB loss abrogates the requirement for amplification of the MAPK signal during malignant progression. We identify CDK2-dependent phosphorylation of RB as an effector of MAPK signalling and critical mediator of resistance to inhibition of CDK4 and CDK6. Second, RB inactivation deregulates the expression of cell-state-determining factors, facilitates lineage infidelity and accelerates the acquisition of metastatic competency. By contrast, reactivation of RB reprograms advanced tumours towards 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 that they control and critical determinants of successful cancer therapy. Loss of RB promotes both malignant progression and the development of metastatic disease; however, whereas reactivation of the RB pathway can revert metastatic tumour cell states to non-metastatic cell states, malignant cell proliferation is supported by MAPK–CDK2-dependent suppression of RB.