The BCL-2 family member BOK promotes KRAS-driven lung cancer progression in a p53-dependent manner
Anna-Lena Meinhardt1,2, Enkhtsetseg Munkhbaatar1,3, Ulrike Höckendorf1
1Department of Medicine III, Klinikum rechts der Isar, TUM School of Medicine, Technical University of Munich, Munich, Germany.
Abstract:
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 KrasG12D-driven murine model of lung cancer. Using KrasG12D/+ 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 KrasG12D-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 KrasG12D/+ Tp53Δ/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.
Insights
BCL-2-related ovarian killer (BOK) promotes KRAS-driven lung cancer progression. Loss of BOK reduces tumor growth and proliferation, highlighting its potential as a therapeutic target in these challenging cancers.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- KRAS mutations drive numerous cancers, presenting significant therapeutic challenges.
- Targeting cancer cell survival pathways, like resistance to cell death, offers a promising strategy for KRAS-mutated cancers.
Purpose of the Study:
- To investigate the role of BCL-2-related ovarian killer (BOK) in KRAS-driven lung cancer.
- To determine if BOK deletion impacts tumor progression in a KrasG12D mouse model.
Main Methods:
- Utilized KrasG12D/+ Bok-/- mice to assess BOK's function in vivo.
- Examined proliferation in vitro and tumor development in vivo.
- Investigated the p53 dependency of BOK's phenotype using KrasG12D/+ Tp53Δ/Δ Bok-/- mice.
- Analyzed human lung tumor datasets for BOK locus deletions.
Main Results:
- Loss of BOK demonstrated a tumor-promoting function in vivo.
- BOK deficiency reduced cancer cell proliferation both in vitro and in KrasG12D-driven tumors.
- Reduced tumor burden, with fewer, smaller, and less advanced tumors, was observed in Bok-/- mice.
- The observed phenotype was dependent on functional p53.
- No common BOK locus deletions were found in human early-stage lung tumors.
Conclusions:
- BOK actively supports tumor progression in KRAS-driven lung cancer.
- BOK represents a potential therapeutic target for KRAS-mutated lung cancers.
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