2. Academic Validation
  3. Simultaneous inhibition of PI3Kα and CDK4/6 synergistically suppresses KRAS-mutated non-small cell lung cancer

Simultaneous inhibition of PI3Kα and CDK4/6 synergistically suppresses KRAS-mutated non-small cell lung cancer

  • Cancer Biol Med. 2019 Feb;16(1):66-83. doi: 10.20892/j.issn.2095-3941.2018.0361.
Yuxiang Wang 1 2,  Xian Li 1,  Xueling Liu 1 2,  Yi Chen 2 3,  Chunhao Yang 4,  Cun Tan 4,  Bobo Wang 1,  Yiming Sun 2 3,  Xi Zhang 1,  Yinglei Gao 2 3,  Jian Ding 2 3,  Linghua Meng 1 2
Affiliations

Affiliations

  • 1 Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200120, China.
PMID: 31119047 DOI: 10.20892/j.issn.2095-3941.2018.0361
Abstract

Objective: Activating KRAS mutations are the most common drivers in the development of non-small cell lung Cancer (NSCLC). However, unsuccess of treatment by direct inhibition of KRAS has been proven. Deregulation of PI3K signaling plays an important role in tumorigenesis and drug resistance in NSCLC. The activity of PI3Kα-selective inhibition against KRAS-mutated NSCLC remains largely unknown.

Methods: Cell proliferation was detected by sulforhodamine B assay. Cell cycle distribution and Apoptosis were measured by flow cytometry. Cell signaling was assessed by Western blot and immunohistochemistry. RNA interference was used to down-regulate the expression of cyclin D1. Human NSCLC xenografts were employed to detect therapeutic efficacy in vivo.

Results: CYH33 possessed variable activity against a panel of KRAS-mutated NSCLC cell lines. Although CYH33 blocked Akt phosphorylation in all tested cells, Rb phosphorylation decreased in CYH33-sensitive, but not in CYH33-resistant cells, which was consistent with G1 phase arrest in sensitive cells. Combined treatment with the CDK4/6 inhibitor, PD0332991, and CYH33 displayed synergistic activity against the proliferation of both CYH33-sensitive and CYH33-resistant cells, which was accompanied by enhanced G1-phase arrest. Moreover, down-regulation of cyclin D1 sensitized NSCLC cells to CYH33. Reciprocally, CYH33 abrogated the PD0332991-induced up-regulation of cyclin D1 and phosphorylation of Akt in A549 cells. Co-treatment with these two drugs demonstrated synergistic activity against A549 and H23 xenografts, with enhanced inhibition of Rb phosphorylation.

Conclusions: Simultaneous inhibition of PI3Kα and CDK4/6 displayed synergistic activity against KRAS-mutated NSCLC. These data provide a mechanistic rationale for the combination of a PI3Kα Inhibitor and a CDK4/6 inhibitor for the treatment of KRAS-mutated NSCLC.

Keywords

CDK4/6; CYH33; KRAS; NSCLC; PI3Kα.

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