A Cereblon Modulator CC-885 Induces CRBN- and p97-Dependent PLK1 Degradation and Synergizes with Volasertib to Suppress Lung Cancer

Abstract

Therapeutic targeting of advanced or metastatic non-small-cell lung cancer (NSCLC) represents a major goal of clinical treatment. Polo-like kinase 1 (PLK1) is an essential mitotic kinase in cell cycle progression and is associated with oncogenesis in a large spectrum of cancer types, including NSCLC. Volasertib (BI 6727) is a potent, selective, PLK1 inhibitor that is currently under phase 2 clinical trials with modest antitumor activity against solid tumors. As the combination of volasertib with pemetrexed does not improve efficacy for NSCLC treatment, it is crucial to identify compounds that could enhance efficacy with volasertib. Immunomodulatory drugs (IMiDs) bind to E3 ligase CRBN and repurposes it to ubiquitinate other proteins as neo-substrates, representing an effective treatment for hematologic malignancies. In this study, by screening IMiDs, we found that a novel CRBN modulator, CC-885, can synergistically inhibit NSCLC with volasertib both in vitro and in vivo . This synergistic effect overcomes volasertib resistance caused by PLK1 mutations and is compromised in CRBN-or p97-depleted cells. Mechanistically, CC-885 selectively promotes CRBN- and p97-dependent PLK1 ubiquitination and degradation, thereby enhancing the sensitivity of NSCLC to volasertib. In conclusion, our findings reveal that PLK1 is a neo-substrate of CUL4-CRBN induced by CC-885 and represent a combinational approach for treating NSCLC.

Ring finger protein 152-dependent degradation of TSPAN12 suppresses hepatocellular carcinoma progression

“…Tandem Ubiquitin Binding Entity 2 (TUBE2) resin (LifeSensors) was used to capture endogenous ubiquitinated proteins [ 14 ]. Cells after transfection were lysed with IP buffer (100 mM NaCl, 20 mM Tris–cl PH8.0, 0.5 mM EDTA, 0.5% (v/v) Nonidet P-40) with protease inhibitor cocktail and phosphorylate inhibitor for 30 min on ice.…”

CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma

“…Another CELMoD, CC-885 has shown anti-cancer activity in several preclinical studies [ 83 , 84 , 95 ]. However, to the best of our knowledge, CC-885 is not yet evaluated in clinical trials.…”

Proteasomal Degradation of Zn-Dependent Hdacs: The E3-Ligases Implicated and the Designed Protacs That Enable Degradation

“…More recently, classical IMiD related compounds have been described as Cereblon Modulators (CELMoDs) ( Figure 6 ) as they fulfill the same substrate-recruiting and CRBN-dependent degradation function as thalidomide, lenalidomide, and pomalidomide. Most of these compounds are in the preclinical phases of development [ 76 , 77 , 78 , 79 , 80 ], but some have already reached clinical trials for the treatment of different types of cancer and autoimmune diseases, such as Avadomide (CC-122) and Iberdomide (CC-220). Avadomide is in Phase I clinical trials for the treatment of diffuse large B-cell (DLBCL) and follicular lymphoma [ 81 ], as well as for the treatment of advanced stages of cancer [ 82 ].…”