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Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status.

ABSTRACT: BACKGROUND:Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028. METHODS:The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo. RESULTS:The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone. CONCLUSIONS:The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status.

SUBMITTER: Chao MW

PROVIDER: S-EPMC6540419 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status.

Chao Min-Wu MW Chang Li-Hsun LH Tu Huang-Ju HJ Chang Chao-Di CD Lai Mei-Jung MJ Chen Yi-Ying YY Liou Jing-Ping JP Teng Che-Ming CM Pan Shiow-Lin SL

Clinical epigenetics 20190529 1

<h4>Background</h4>Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028.<h4>Methods</h4>The effects of combined therapy o ...[more]

PMID: 31142371

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Project description:BACKGROUND:This multicenter, open-label, phase Ib study investigated the safety and efficacy of binimetinib (MEK inhibitor) in combination with buparlisib (phosphatidylinositol 3-kinase [PI3K] inhibitor) in patients with advanced solid tumors with RAS/RAF alterations. MATERIALS AND METHODS:Eighty-nine patients were enrolled in the study. Eligible patients had advanced solid tumors with disease progression after standard therapy and/or for which no standard therapy existed. Evaluable disease was mandatory, per RECIST version 1.1 and Eastern Cooperative Oncology Group performance status 0-2. Binimetinib and buparlisib combinations were explored in patients with KRAS-, NRAS-, or BRAF-mutant advanced solid tumors until the maximum tolerated dose and recommended phase II dose (RP2D) were defined. The expansion phase comprised patients with epidermal growth factor receptor (EGFR)-mutant, advanced non-small cell lung cancer, after progression on an EGFR inhibitor; advanced RAS- or BRAF-mutant ovarian cancer; or advanced non-small cell lung cancer with KRAS mutation. RESULTS:At data cutoff, 32/89 patients discontinued treatment because of adverse events. RP2D for continuous dosing was buparlisib 80 mg once daily/binimetinib 45 mg twice daily. The toxicity profile of the combination resulted in a lower dose intensity than anticipated. Six (12.0%) patients with RAS/BRAF-mutant ovarian cancer achieved a partial response. Pharmacokinetics of binimetinib were not altered by buparlisib. Pharmacodynamic analyses revealed downregulation of pERK and pS6 in tumor biopsies. CONCLUSION:Although dual inhibition of MEK and the PI3K pathways showed promising activity in RAS/BRAF ovarian cancer, continuous dosing resulted in intolerable toxicities beyond the dose-limiting toxicity monitoring period. Alternative schedules such as pulsatile dosing may be advantageous when combining therapies. IMPLICATIONS FOR PRACTICE:Because dysregulation of the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K) pathways are both frequently involved in resistance to current targeted therapies, dual inhibition of both pathways may be required to overcome resistance mechanisms to single-agent tyrosine kinase inhibitors or to treat cancers with driver mutations that cannot be directly targeted. A study investigating the safety and efficacy of combination binimetinib (MEK inhibitor) and buparlisib (PI3K inhibitor) in patients harboring alterations in the RAS/RAF pathway was conducted. The results may inform the design of future combination therapy trials in patients with tumors harboring mutations in the PI3K and MAPK pathways.

Dataset Information

Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status.

Publications

Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status.

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