The BCL-2 family member BOK promotes KRAS-driven lung cancer progression in a p53-dependent manner.
Anna-Lena MeinhardtEnkhtsetseg MunkhbaatarUlrike HöckendorfMichelle DietzenMarta DechantMartina AntonAnne JacobKatja SteigerWilko WeichertLuka BrcicNicholas McGranahanCaterina BrancaThomas KaufmannMichael A DenglerPhilipp J JostPublished in: Oncogene (2022)
A variety of cancer entities are driven by KRAS mutations, which remain difficult to target clinically. Survival pathways, such as resistance to cell death, may represent a promising treatment approach in KRAS mutated cancers. Based on the frequently observed genomic deletions of BCL-2-related ovarian killer (BOK) in cancer patients, we explored the function of BOK in a mutant Kras G12D -driven murine model of lung cancer. Using Kras G12D/+ Bok -/- mice, we observed an overall tumor-promoting function of BOK in vivo. Specifically, loss of BOK reduced proliferation both in cell lines in vitro as well as in Kras G12D -driven tumor lesions in vivo. During tumor development in vivo, loss of BOK resulted in a lower tumor burden, with fewer, smaller, and less advanced tumors. Using Kras G12D/+ Tp53 Δ/Δ Bok -/- mice, we identified that this phenotype was entirely dependent on the presence of functional p53. Furthermore, analysis of a human dataset of untreated early-stage lung tumors did not identify any common deletion of the BOK locus, independently of the TP53 status or the histopathological classification. Taken together our data indicate that BOK supports tumor progression in Kras-driven lung cancer.
Keyphrases
- wild type
- early stage
- cell death
- type diabetes
- machine learning
- endothelial cells
- signaling pathway
- gene expression
- radiation therapy
- squamous cell carcinoma
- poor prognosis
- dna methylation
- metabolic syndrome
- cell proliferation
- electronic health record
- skeletal muscle
- drug induced
- neoadjuvant chemotherapy
- high fat diet induced
- copy number