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PI3K-targeting strategy using alpelisib to enhance the antitumor effect of paclitaxel in human gastric cancer.

ABSTRACT: PIK3CA mutations are frequently observed in various human cancers including gastric cancer (GC). This study was conducted to investigate the anti-tumor effects of alpelisib, a PI3K p110α-specific inhibitor, using preclinical models of GC. In addition, the combined effects of alpelisib and paclitaxel on GC were evaluated. Among the SNU1, SNU16, SNU484, SNU601, SNU638, SNU668, AGS, and MKN1 GC cells, three PIK3CA-mutant cells were predominantly sensitive to alpelisib. Alpelisib monotherapy decreased AKT and S6K1 phosphorylation and induced G₀/G₁ phase arrest regardless of PIK3CA mutational status. The alpelisib and paclitaxel combination demonstrated synergistic anti-proliferative effects, preferentially on PIK3CA-mutant cells, resulting in increased DNA damage response and apoptosis. In addition, alpelisib and paclitaxel combination potentiated anti-migratory activity in PIK3CA-mutant cells. Alpelisib partially reversed epithelial-mesenchymal transition markers in PIK3CA-mutant cells. In a xenograft model of MKN1 cells, the alpelisib and paclitaxel combination significantly enhanced anti-tumor activity by decreasing Ki-67 expression and increasing apoptosis. Moreover, this combination tended to prolong the survival of tumor-bearing mice. Our data suggest promising anti-tumor efficacy of alpelisib alone or in combination with paclitaxel in PIK3CA-mutant GC cells.

SUBMITTER: Kim KJ

PROVIDER: S-EPMC7378194 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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PI3K-targeting strategy using alpelisib to enhance the antitumor effect of paclitaxel in human gastric cancer.

Kim Kui-Jin KJ Kim Ji-Won JW Sung Ji Hea JH Suh Koung Jin KJ Lee Ji Yun JY Kim Se Hyun SH Lee Jeong-Ok JO Kim Jin Won JW Kim Yu Jung YJ Kim Jee Hyun JH Bang Soo-Mee SM Lee Jong Seok JS Kim Hark Kyun HK Lee Keun-Wook KW

Scientific reports 20200723 1

PIK3CA mutations are frequently observed in various human cancers including gastric cancer (GC). This study was conducted to investigate the anti-tumor effects of alpelisib, a PI3K p110α-specific inhibitor, using preclinical models of GC. In addition, the combined effects of alpelisib and paclitaxel on GC were evaluated. Among the SNU1, SNU16, SNU484, SNU601, SNU638, SNU668, AGS, and MKN1 GC cells, three PIK3CA-mutant cells were predominantly sensitive to alpelisib. Alpelisib monotherapy decreas ...[more]

PMID: 32704014

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Project description:Trastuzumab emtansine (T-DM1), an antibody-drug conjugate consisted of the HER2-targeted monoclonal antibody trastuzumab and the tubulin inhibitor emtansine, has shown potent therapeutic value in HER2-positive breast cancer (BC). However, a clinical trial indicated that T-DM1 exerts a limited effect on HER2-positive gastric cancer (GC), but the underlying mechanism is inconclusive. Our research attempted to reveal the probable mechanism and role of autophagy in T-DM1-treated HER2-positive GC. In this study, our results showed that T-DM1 induced apoptosis and exhibited potent therapeutic efficacy in HER2-positive GC cells. In addition, autophagosomes were observed by transmission electron microscopy. Autophagy was markedly activated and exhibited the three characterized gradations of autophagic flux, consisting of the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and the deterioration of autophagosomes in autolysosomes. More importantly, autophagic inhibition by the suppressors 3-methyladenine (3-MA) and LY294002 significantly potentiated cytotoxicity and apoptosis in HER2-positive GC cells in vitro, while the combined use of LY294002 and T-DM1 elicited potent anti-GC efficacy in vivo. In mechanistic experiments, immunoblot analysis indicated the downregulated levels of Akt, mTOR, and P70S6K and confocal microscopy analysis clearly showed that autophagic inhibition promoted the fusion of T-DM1 molecules with lysosomes in GC cells. In conclusion, our research demonstrated that T-DM1 induced apoptosis as well as cytoprotective autophagy, and autophagic inhibition could potentiate the antitumor effect of T-DM1 on HER2-positive GC. Furthermore, autophagic inhibition might increase the fusion of T-DM1 with lysosomes, which might accelerate the release of the cytotoxic molecule emtansine from the T-DM1 conjugate. These findings highlight a promising therapeutic strategy that combines T-DM1 with an autophagy inhibitor to treat HER-positive GC more efficiently.

Project description:PurposePIK3CA mutations are common in breast cancer and promote tumor progression and treatment resistance. We conducted a phase I/II trial of alpelisib (α-specific PI3K inhibitor) plus nab-paclitaxel in patients with HER2-negative metastatic breast cancer (MBC).Patients and methodsEligible patients had HER2-negative MBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of alpelisib (250, 300, and 350 mg) daily plus nab-paclitaxel 100 mg/m2 administered on days 1, 8, and 15 every 28 days. Phase II was according to Simon's two-stage design. PIK3CA mutations in tumor/circulating tumor DNA (ctDNA) were assessed. Primary endpoints were recommended phase II dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, pharmacokinetics, progression-free survival (PFS), and association of PIK3CA mutation with outcomes.ResultsA total of 43 patients were enrolled (phase I, n = 13 and phase II, n = 30). A total of 84% had visceral disease and 84% had prior taxane. No dose-limiting toxicities occurred in phase I. RP2D was alpelisib 350 mg daily plus nab-paclitaxel 100 mg/m2 on days 1, 8, and 15. Hyperglycemia (grade 3, 26% and grade 4, 0%), neutropenia (grade 3, 23% and grade 4, 7%), diarrhea (grade 3, 5% and grade 4, 0%), and rash (grade 3, 7% and grade 4, 0%) were the most common adverse events. Among 42 evaluable patients, ORR was 59% (complete response, 7% and partial response, 52%), 21% of whom had response lasting >12 months; median PFS was 8.7 months. A total of 40% of patients demonstrated tumor and/or ctDNA PIK3CA mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared with those without mutation (11.9 vs. 7.5 months; HR, 0.44; P = 0.027). Patients with normal metabolic status had longer PFS compared with prediabetic/diabetic patients (12 vs. 7.5 months; P = 0.014). No pharmacokinetics interactions were detected.ConclusionsThe alpelisib plus nab-paclitaxel combination was well tolerated and shows encouraging efficacy, especially in patients with PIK3CA-mutated tumor/ctDNA. The impact of metabolic status on response to this combination merits further investigation.

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PI3K-targeting strategy using alpelisib to enhance the antitumor effect of paclitaxel in human gastric cancer.

Publications

PI3K-targeting strategy using alpelisib to enhance the antitumor effect of paclitaxel in human gastric cancer.

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