Abstract
Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effectively synergized to inhibit proliferation, survival and invasion in the majority of ovarian cancer cell lines harboring PIK3CA mutations, including SKOV3, HEYA8, and IGROV1. Mechanistically, combined treatment of PARP and PI3K inhibitors resulted in an exacerbated DNA damage response and more substantially reduced AKT/mTOR signaling when compared to single-agent. Notably, ovarian cancer cells responsive to the PI3K/PARP combination displayed decreased BRCA1/2 expression upon drug treatment. Furthermore, the effect of the drug combination was corroborated in an intraperitoneal dissemination xenograft mouse model in which SKOV3 ovarian cancer cells responded with significantly decreased BRCA1 expression, suppressed PI3K/AKT signaling and reduced tumor burden. Collectively, our data suggested that combined inhibition of PI3K and PARP may be an effective therapeutic strategy for ovarian cancers with PIK3CA mutations and that the accompanied BRCA downregulation following PI3K inhibition could serve as a biomarker for the effective response to PARP inhibition.
Highlights
The PI3K pathway is an important signaling network that regulates critical cellular functions including cell growth, proliferation and survival [1, 2]
While BKM120 effectively inhibited the growth of majority of the ovarian cancer cell lines examined, we failed to identify an apparent association between a particular genetic alteration (i.e. PIK3CA, K-Ras, p53, PTEN, and EGFR) [22] and cellular response to BKM120 treatment (Figure S1A and S1B)
Given that BKM120 rendered PIK3CA mutated ovarian cancer cells more deficient in homologous recombination (HR) repair (Figure S2B), we hypothesized that combined inhibition of PI3K and poly (ADP-ribose) polymerase (PARP) may lead to a stronger therapeutic effect than BKM120 as singe-agent
Summary
The PI3K pathway is an important signaling network that regulates critical cellular functions including cell growth, proliferation and survival [1, 2]. PIK3CA mutations mainly occur in the kinase domain (H1047R) and the helical domain (E542K or E545K) of p110α, with H1047R being the most common mutation [1] These tumor-associated PIK3CA mutations result in constitutive activation of p110α and its downstream effector AKT signaling with consequent oncogenic transformation [2]. A number of PI3K inhibitors have shown significant antitumor activities either as single-agents or when used in combination with cytotoxic anti-cancer agents in in vitro and in vivo models of ovarian cancers [5, 6]. BKM120, a pan-class I PI3K inhibitor currently in Phase I/II clinical trials [8, 9], has demonstrated anti-proliferative, proapoptotic, and antitumor activity in a variety of cell lines and xenograft models from cancers with and without aberrant PI3K pathway activation [10, 11]. PI3K suppression has been shown to impair homologous recombination (HR) in the cellular DNA damage response pathway [12, 13]
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