PBRM1 Deficiency Sensitizes Renal Cancer Cells to DNMT Inhibitor 5-Fluoro-2’-Deoxycytidine

Abstract

PBRM1 is a tumor suppressor frequently mutated in clear cell renal cell carcinoma. However, no effective targeted therapies exist for ccRCC with PBRM1 loss. To identify novel therapeutic approaches to targeting PBRM1-deficient renal cancers, we employed a synthetic lethality compound screening in isogenic PBRM1+/+ and PBRM1-/- 786-O renal tumor cells and found that a DNMT inhibitor 5-Fluoro-2’-deoxycytidine (Fdcyd) selectively inhibit PBRM1-deficient tumor growth. RCC cells lacking PBRM1 show enhanced DNA damage response, which leads to sensitivity to DNA toxic drugs. Fdcyd treatment not only induces DNA damage, but also re-activated a pro-apoptotic factor XAF1 and further promotes the genotoxic stress-induced PBRM1-deficient cell death. This study shows a novel synthetic lethality interaction between PBRM1 loss and Fdcyd treatment and indicates that DNMT inhibitor represents a novel strategy for treating ccRCC with PBRM1 loss-of-function mutations.

Advances in the role of SWI/SNF complexes in tumours

“… 31 Furthermore, mutations in PBRM1 are also associated with pancreatic cancer (PDAC), advanced gastric cancer (GC), cervical cancer (CCA) and other tumour formation related. 32 , 33 , 34 , 35 , 36 BRD7, SMARCC2, ARID2, ACTL6A/B, SMARCC1, SMARCD1/2/3 are other key subunits of SWI/SNF, and recent studies have reported that mutations in these subunits cause gastric cancer (GC), colon cancer (CRC), hepatocellular carcinoma (HCC), head and neck squamous carcinoma (HSNC), breast cancer (BRCA) and other tumours. 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 In addition, genes encoding tumour‐associated subunits of the SWI/SNF complex, such as BAF57/SMARCE1, are heterozygous for mutations or completely lost in familial spinal meningioma cases.…”

“…31 Furthermore, mutations in PBRM1 are also associated with pancreatic cancer (PDAC), advanced gastric cancer (GC), cervical cancer (CCA) and other tumour formation related. [32][33][34][35][36] [20][21][22][23][24][25][26][27][28][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] In addition, genes encoding tumour-associated subunits of the SWI/SNF complex, such as BAF57/SMARCE1, are heterozygous for mutations or completely lost in familial spinal meningioma cases. 31 Some of these tumours contain mutations in more than one subunit, such as renal cell carcinoma, breast cancer, and colon cancer, suggesting that the development of a cancer may be caused by mutations in one or more subunits of the SWI/ SNF complex.…”

“…PBRM1, a target subunit of PBAF, is a common oncogene with a 40% mutation rate in renal cell carcinoma, and our previous study found that deletion of PBRM1 could activate the AKT pathway and glycolytic pathway and thus affect the function of ccRCC cells 31 . Furthermore, mutations in PBRM1 are also associated with pancreatic cancer (PDAC), advanced gastric cancer (GC), cervical cancer (CCA) and other tumour formation related 32–36 . BRD7, SMARCC2, ARID2, ACTL6A/B, SMARCC1, SMARCD1/2/3 are other key subunits of SWI/SNF, and recent studies have reported that mutations in these subunits cause gastric cancer (GC), colon cancer (CRC), hepatocellular carcinoma (HCC), head and neck squamous carcinoma (HSNC), breast cancer (BRCA) and other tumours 20–28,37–53 .…”