The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer.

AXL is a receptor tyrosine kinase that is often overexpressed in cancers. It contributes to pathophysiology in cancer progression and therapeutic resistance, making it an emerging therapeutic target. The first-in-class AXL inhibitor bemcentinib (R428/BGB324) has been granted fast track designation by the U.S. Food and Drug Administration (FDA) in STK11-mutated advanced metastatic non-small cell lung cancer and was also reported to show selective sensitivity towards ovarian cancers (OC) with a Mesenchymal molecular subtype. In this study, we further explored AXL's role in mediating DNA damage responses by using OC as a disease model. AXL inhibition using R428 resulted in the increase of DNA damage with the concurrent upregulation of DNA damage response signalling molecules. Furthermore, AXL inhibition rendered cells more sensitive to the inhibition of ATR, a crucial mediator for replication stress. Combinatory use of AXL and ATR inhibitors showed additive effects in OC. Through SILAC co-immunoprecipitation mass spectrometry, we identified a novel binding partner of AXL, SAM68, whose loss in OC cells harboured phenotypes in DNA damage responses similar to AXL inhibition. In addition, AXL- and SAM68-deficiency or R428 treatment induced elevated levels of cholesterol and upregulated genes in the cholesterol biosynthesis pathway. There might be a protective role of cholesterol in shielding cancer cells against DNA damage induced by AXL inhibition or SMA68 deficiency.

PBRM1-deficient PBAF complexes target aberrant genomic loci to activate the NF-κB pathway in clear cell renal cell carcinoma.

PBRM1 encodes an accessory subunit of the PBAF SWI/SNF chromatin remodeller, and the inactivation of PBRM1 is a frequent event in kidney cancer. However, the impact of PBRM1 loss on chromatin remodelling is not well examined. Here we show that, in VHL-deficient renal tumours, PBRM1 deficiency results in ectopic PBAF complexes that localize to de novo genomic loci, activating the pro-tumourigenic NF-κB pathway. PBRM1-deficient PBAF complexes retain the association between SMARCA4 and ARID2, but have loosely tethered BRD7. The PBAF complexes redistribute from promoter proximal regions to distal enhancers containing NF-κB motifs, heightening NF-κB activity in PBRM1-deficient models and clinical samples. The ATPase function of SMARCA4 maintains chromatin occupancy of pre-existing and newly acquired RELA specific to PBRM1 loss, activating downstream target gene expression. Proteasome inhibitor bortezomib abrogates RELA occupancy, suppresses NF-κB activation and delays growth of PBRM1-deficient tumours. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumourigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes.

Shifting the Gears of Metabolic Plasticity to Drive Cell State Transitions in Cancer.

Cancer metabolism is a hallmark of cancer. Metabolic plasticity defines the ability of cancer cells to reprogram a plethora of metabolic pathways to meet unique energetic needs during the various steps of disease progression. Cell state transitions are phenotypic adaptations which confer distinct advantages that help cancer cells overcome progression hurdles, that include tumor initiation, expansive growth, resistance to therapy, metastasis, colonization, and relapse. It is increasingly appreciated that cancer cells need to appropriately reprogram their cellular metabolism in a timely manner to support the changes associated with new phenotypic cell states. We discuss metabolic alterations that may be adopted by cancer cells in relation to the maintenance of cancer stemness, activation of the epithelial-mesenchymal transition program for facilitating metastasis, and the acquisition of drug resistance. While such metabolic plasticity is harnessed by cancer cells for survival, their dependence and addiction towards certain metabolic pathways also present therapeutic opportunities that may be exploited.