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.