The BCL-2 family member BOK promotes KRAS-driven lung cancer progression in a p53-dependent manner

Anna-Lena Meinhardt,Ulrike Höckendorf,Thomas Kaufmann,Anne Jacob,Martina Anton,Michael A Dengler,Caterina Branca,Wilko Weichert,Nicholas Mcgranahan,Luka Brcic,Marta Dechant,Katja Steiger,Michelle Dietzen,Philipp J Jost,Enkhtsetseg Munkhbaatar

doi:10.1038/s41388-021-02161-1

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/ΔBok−/− 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.

Highlights

Despite recent therapeutic advances, including the development of immune checkpoint inhibitors and other targeted therapies, lung cancer remains the leading cause of cancer-related deaths worldwide [1]
Bok deletion reduces tumor burden driven mouse lung adenocarcinoma cell line LKR10 [22] to generate Bok-deficient cells by CRISPR/Cas9 (LKR10 Bok−/− and, To analyze the role of BCL-2-related ovarian killer (BOK) in lung cancer, we used mice harboring a lox-stop-lox-KrasG12D allele, in which the mutated Kras is as control, LKR10 LacZ, Fig. S2a)
Functional Tp53 mediates the Bok− dependent phenotype Since alterations in the TP53 tumor suppressor gene occur in about 50% of NSCLC cases [23], we investigated the contribution of functional p53 signaling to the effects of BOK in lung adenocarcinoma by crossing the KrasG12D Bok−/− mice in a Tp53fl/fl background

Summary

Introduction

Despite recent therapeutic advances, including the development of immune checkpoint inhibitors and other targeted therapies, lung cancer remains the leading cause of cancer-related deaths worldwide [1]. About 33% of LUAD cases are associated with activating mutations in KRAS [2], which are difficult to target in a clinical setting. 46% of LUAD patients have somatic mutations in the tumor suppressor TP53––one of the most common events in cancer [2]. Defects in apoptosis can promote tumorigenesis per se through extending the life span of a cell, increasing its chances of acquiring additional cancer-promoting mutations [5]. Apoptosis inhibition enables cell resistance to stress caused by oncogenic alterations, nutrient deprivation, DNA damage, or the build-up of toxic components [6]. Apoptosis is controlled by the BCL-2 protein family [7], which comprises both pro- and anti-apoptotic members. Several cancer entities have altered expression of BCL-2 family members [7,8,9]

Methods

Results

Conclusion