CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib

Abstract

Effective targeted therapies for small-cell lung cancer (SCLC), the most aggressive form of lung cancer, remain urgently needed. Here we report evidence of preclinical efficacy evoked by targeting the overexpressed cell-cycle checkpoint kinase CHK1 in SCLC. Our studies employed RNAi-mediated attenuation or pharmacologic blockade with the novel second-generation CHK1 inhibitor prexasertib (LY2606368), currently in clinical trials. In SCLC models in vitro and in vivo, LY2606368 exhibited strong single-agent efficacy, augmented the effects of cisplatin or the PARP inhibitor olaparib, and improved the response of platinum-resistant models. Proteomic analysis identified CHK1 and MYC as top predictive biomarkers of LY2606368 sensitivity, suggesting that CHK1 inhibition may be especially effective in SCLC with MYC amplification or MYC protein overexpression. Our findings provide a preclinical proof of concept supporting the initiation of a clinical efficacy trial in patients with platinum-sensitive or platinum-resistant relapsed SCLC.

Cyclin E expression is associated with high levels of replication stress in triple-negative breast cancer

“…These findings are in line with previous reports, showing frequent MYC amplification in TNBC 29 . Importantly, our results provide confirmation that the link between c-Myc-overexpression and induction of replication stress is also observed in patient samples 12,31,42 .…”

Poly ADP‐ribose polymerase‐1 as a potential therapeutic target in Merkel cell carcinoma

“…Given the recent approval of avelumab for patients with incurable Merkel cell carcinoma and the growing body of evidence demonstrating an increased therapeutic efficacy of PARP inhibitors combined with anti‐ programmed death ligand‐1, this combination deserves clinical investigation in patients with this orphan disease . Other combinations, such as PARP inhibitors and chemotherapy, phosphotidylinositol‐3‐kinase inhibitors, or CHK1 inhibitors has shown promising activity in SCLC and may be clinically active in Merkel cell carcinoma.…”

Targeting DNA damage in SCLC

“…In preclinical studies, prexasertib has activity as a single agent and works synergistically with cytotoxic DNA damaging agents, inducing cell death in SCLC models [73]. A phase I trial of prexasertib in patients with advanced refractory squamous NSCLC, head and neck cancers and anal cancers reported a partial response (PR) of 4.4% (2/ 45) and SD in 33% (15/45) [74].…”