SETD2 loss sensitizes cells to PI3Kβ and AKT inhibition

Abstract

Upregulation of the PI3K pathway has been implicated in the initiation and progression of several types of cancer, including renal cell carcinoma (RCC). Although several targeted therapies have been developed for RCC, durable and complete responses are exceptional. Thus, advanced RCC remains a lethal disease, underscoring the need of robust biomarker-based strategies to treat RCC. We report a synthetic lethal interaction between inhibition of phosphatidylinositol 3-kinase beta (PI3Kβ) and loss of SETD2 methyltransferase. Clear cell RCC (ccRCC)-derived SETD2 knockout 786-0 and SETD2 mutant A498 cells treated with TGX221 (PI3Kβ-specific) and AZD8186 (PI3Kβ- and δ-specific) inhibitors displayed decreased cell viability, cell growth, and migration compared to SETD2 proficient 786-0 cells. Inhibition of the p110 δ and α isoforms alone had modest (δ) and no (α) effect on ccRCC cell viability, growth, and migration. In vivo, treatment of SETD2 mutant A498 cells, but not SETD2 proficient 786-0 cells, with AZD8186 significantly decreased tumor growth. Interestingly, inhibition of the downstream effector AKT (MK2206) recapitulated the effects observed in AZD8186-treated SETD2 deficient cells. Our data show that specific inhibition of PI3Kβ causes synthetic lethality with SETD2 loss and suggest targeting of the AKT downstream effector pathway offers a rationale for further translational and clinical investigation of PI3Kβ-specific inhibitors in ccRCC.

Multiomics characterization and verification of clear cell renal cell carcinoma molecular subtypes to guide precise chemotherapy and immunotherapy

“…For patients in MoS1 subtype, axitinib, GDC0941, and dimethyloxalylglycine are more likely to delay progression of ccRCC. PI3K‐AKT pathway was widely reported as a promising druggable target in SETD2‐deficient ccRCC [ 71 ], indicating the inhibitors of PI3K‐AKT pathway might be suitable for MoS1 and MoS2 subtypes for their high SETD2 mutations, and based on GDSC online website, we identified several drugs for MoS1 as well, such as AZD8186, AZD5653, and Alpelisib. Collectively, the results mentioned above suggested MoSs classifier might be a potential tool for developing individualized treatment strategies for different patients.…”

Epigenetic synthetic lethality approaches in cancer therapy

“…Terzo et al also reported that there is a synthetic lethal interaction between SETD2-deficiency and PI3Kβ-AKT inhibition in kidney cancer [50]. The phosphoinositide 3-kinase (PI3K)-AKT axis is a very important signaling pathway in cell proliferation and it is frequently changed in cancers [51].…”

Clinical, pathologic and molecular findings in 2 Rottweiler littermates with appendicular osteosarcoma

“…SETD2 loss or inactivation has been associated with enhanced response to mTOR inhibition through alterations in oxidative metabolism and protein synthesis pathways. 73,74 Shared loss of NOTCH1 in both dogs also carries relevance to osteosarcoma, as the NOTCH signaling pathway plays an important role in osteogenic differentiation. 75 Dysregulation of this pathway is linked to occurrence and progression of defects involving this process.…”