Synthetic Lethality Screening Highlights Colorectal Cancer Vulnerability to Concomitant Blockade of NEDD8 and EGFR Pathways

Abstract

Colorectal cancer (CRC) is a heterogeneous disease showing significant variability in clinical aggressiveness. Primary and acquired resistance limits the efficacy of available treatments, and identification of effective drug combinations is needed to further improve patients’ outcomes. We previously found that the NEDD8-activating enzyme inhibitor pevonedistat induced tumor stabilization in preclinical models of poorly differentiated, clinically aggressive CRC resistant to available therapies. To identify drugs that can be effectively combined with pevonedistat, we performed a “drop-out” loss-of-function synthetic lethality screening with an shRNA library covering 200 drug-target genes in four different CRC cell lines. Multiple screening hits were found to be involved in the EGFR signaling pathway, suggesting that, rather than inhibition of a specific gene, interference with the EGFR pathway at any level could be effectively leveraged for combination therapies based on pevonedistat. Exploiting both BRAF-mutant and RAS/RAF wild-type CRC models, we validated the therapeutic relevance of our findings by showing that combined blockade of NEDD8 and EGFR pathways led to increased growth arrest and apoptosis both in vitro and in vivo. Pathway modulation analysis showed that compensatory feedback loops induced by single treatments were blunted by the combinations. These results unveil possible therapeutic opportunities in specific CRC clinical settings.

Regulated cell death (RCD) in cancer: key pathways and targeted therapies

“… 435 In BRAF-mutant and RAS/RAF wild-type CRC cells, double blocking of NEDD8 and EGFR pathways led to cell growth arrest and increased apoptosis induction. 436 Sun et al reported the novel synthetic lethal partners, Src and PARP1, that exerted a pronounced anticancer effect on HCC cells and could suppress the resistance to PARP1 inhibition. 437 Moreover, a combination of sorafenib and selumetinib was also an effective therapy in HCC cells having high p-ERK levels.…”

Case report: Preclinical efficacy of NEDD8 and proteasome inhibitors in patient-derived models of signet ring high-grade mucinous colorectal cancer from a Lynch syndrome patient

“…Examples include combination of bortezomib with vorinostat and dexamethasone in relapsed multiple myeloma [NCT01720875 ( 34 )]. Pevonedistat was found to synergize with EGFR pathway inhibition, leading to tumor regression, in CRC xenograft models ( 35 ). Bortezomib and pevonedistat could also increase the efficacy of immunotherapy, because both drugs have been shown to induce immunogenic cell death, potentially enhancing antitumor immunity and allowing more durable responses to immunotherapy ( 36 , 37 ).…”

Targeting neddylation as a novel approach to lung cancer treatment (Review)

“…It may also participate in tumorigenesis, growth and metastasis by regulating multiple signaling pathways. There is a strong association between NEDD8 overactivation and cancer progression in lung cancer, breast cancer (51), liver cancer (71) and colorectal cancer (72). NEDD8-mediated upregulation of neddylation has been found in lung cancer, affecting the prognosis and treatment of patients.…”

“…NEDD8-mediated neddylation is closely related to the occurrence and development of tumors. Overexpression of neddylation-related proteins has been seen in lung cancer (30), breast cancer (51), liver cancer (71) and colorectal cancer (72) and may significantly reduce the overall survival rate of patients. To date, it has been found that the expression pattern of NEDD8-related proteins has changed in cancerous lung tissues, including large-cell neuroendocrine carcinoma of the lung (LCNEC), lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) (73).…”