Recently, a research team led by Prof. Lin Wenchu from High Magnetic Field Laboratory, Hefei Institutes of Physical Science found that CUDC-907, a dual PI3K and HDAC inhibitor, exerted antitumor effect in small cell lung cancer (SCLC). And the effect was more prominent when combined with olaparib, a common clinical drug. Targeting DSB repaired pathways with dual HDAC-PI3K inhibitors was a promising strategy to improve PARPi efficacy and therapeutic benefits for patients with SCLC.

SCLC, characterized by rapid tumor growth and early metastasis, represents one of the deadliest cancer types among all solid tumor malignancies. Nearly all SCLC patients eventually develop resistance to previously effective therapies, leading to a five-year survival rate at less than 7%.

In this research, CUDC-907 treatment downregulated MYC paralogs and FoxM1, induced G1 cell-cycle arrest, and impaired DNA double-strand break (DSB) repair capacity in SCLC cells, which produced a potent antiproliferative effect. Furthermore, they showed that CUDC-907 treatment enhanced the therapeutic efficacy of PARP inhibitor olaparib in a panel of SCLC cellular models and a PDX model. Mechanistic investigations demonstrated that CUDC-907 synergized with olaparib through the blockade of DSB repair pathways and downregulation of MYC paralogs and FoxM1.

This investigation was supported by National Natural Science Foundation of China (Grant Numbers: 81972191 and 81672647), Science and Technology Major Project of Anhui Province (Grant Number: 18030801140), A portion of this work was supported by the High Magnetic Field Laboratory of Anhui Province.

Link to the paper:The dual HDAC-PI3K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in small cell lung cancer

Fig.1 A strong synergistic effect of CUDC-907 and olaparib in SCLC cells (Image by Liying Ma)

Fig.2 The combined use of CUDC-907 and olaparib effectively suppresses tumor growth in a PDX model of SCLC (Image by Liying Ma)

Contact:

ZHAO Weiwei
Hefei Institutes of Physical Science (http://english.hf.cas.cn/)
Email: annyzhao@ipp.ac.cn