Safety and efficacy study of oral metronomic capecitabine combined with pyrotinib in HER2-positive metastatic breast cancer: A phase II trial

Purpose: To analyze the safety and efficacy of orally administered metronomic capecitabine plus pyrotinib in HER2 positive metastatic breast cancer (MBC) patients, we conducted a prospective phase II study with a single-arm design. Methods: HER2 positive patients received oral metronomic capecitabine 500 mg three times a day and pyrotinib 400 mg per day. The primary endpoint was progression-free survival (PFS). Other endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR) and safety. Results: The study included 50 patients with MBC that was HER2-positive, while 1 patient was excluded due to nonstandard medication. The median PFS and OS was 11.9 months (95%CI 8.8–14.6) and 29.3 months (95%CI 24.4–34.8) respectively. ORR was 34.7%, and CBR was 81.6% with 2 CR (4.1%), 15 PR (30.6%) and 23 SD (46.9%). The mPFS in first- or second-line treatment was 12.2 months. The most frequent treatment-related adverse events included hand-foot syndrome, diarrhea, vomiting and nausea. Grade 3 adverse events occurred in 15(30.6%) patients, including hand-foot syndrome (12.2%), diarrhea (12.2%), vomiting (4.1%), and nausea (2.0%). 1 grade 4 adverse event of diarrhea (2.0%) was observed. Conclusion: The combination of metronomic capecitabine and pyrotinib is a promising regimen with competitive efficacy and improved tolerability in HER2 positive metastatic breast cancer patients

MTA1, a Novel ATP Synthase Complex Modulator, Enhances Colon Cancer Liver Metastasis by Driving Mitochondrial Metabolism Reprogramming

Abstract Liver metastasis is the most fatal event of colon cancer patients. Warburg effect has been long challenged by the fact of upregulated oxidative phosphorylation (OXPHOS), while its mechanism remains unclear. Here, metastasis‐associated antigen 1 (MTA1) is identified as a newly identified adenosine triphosphate (ATP) synthase modulator by interacting with ATP synthase F1 subunit alpha (ATP5A), facilitates colon cancer liver metastasis by driving mitochondrial bioenergetic metabolism reprogramming, enhancing OXPHOS; therefore, modulating ATP synthase activity and downstream mTOR pathways. High‐throughput screening of an anticancer drug shows MTA1 knockout increases the sensitivity of colon cancer to mitochondrial bioenergetic metabolism‐targeted drugs and mTOR inhibitors. Inhibiting ATP5A enhances the sensitivity of liver‐metastasized colon cancer to sirolimus in an MTA1‐dependent manner. The therapeutic effects are verified in xenograft models and clinical cases. This research identifies a new modulator of mitochondrial bioenergetic reprogramming in cancer metastasis and reveals a new mechanism on upregulating mitochondrial OXPHOS as the reversal of Warburg effect in cancer metastasis is orchestrated

Additional file 11 of S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer

Additional file 11: Supplementary Fig. S4. Related to Fig. 6. (A) xCELLigence system analysis of the proliferation of MCF-7 cells treated with either vehicle, palbociclib (5 μM), rapamycin (1 μM) or combination. (B) S6K1-amplified PDOs from breast cancers showed limited response to everolimus or palbociclib as monotherapy. Data are presented as the mean ± SEM; P value was calculated by 2-way ANOVA. (C) Dose–response matrix for the effect of palbociclib plus mTOR inhibitor (everolimus) in a S6K1-amplificated organoid derived from breast cancer patient. (D) Tumour growth inhibition (TGI) curve in S6K1-amplificated xenograft derived from breast cancer patient. Data are presented as the mean ± SEM; P value was calculated by Mixed-effects model. *, P < 0.05. TGI was calculated using the following formula: TGI = 1 − (tumour volume change of the treated group relative to day 0)/(tumour volume change of the control group relative to day 0)

Additional file 12 of S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer

Additional file 12: Supplementary Fig. S5. Schematic representation of the proposed signal transduction pathways in S6K1-mediated cell proliferation and resistance to CDK4/6 inhibitors. Figures made in ©BioRender-biorender.com

Additional file 2 of S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer

Additional file 2: Supplementary Table S2. The copy number variation of S6K1 gene (S6K1:CEP17 via ddPCR) in patients with low S6K1 expression