Dataset Information

Metastatic Colorectal Cancer Patient With Microsatellite Stability and BRAF^V600E Mutation Showed a Complete Metabolic Response to PD-1 Blockade and Bevacizumab: A Case Report.

ABSTRACT: A vast majority of colorectal cancer (CRC) patients with microsatellite stability (MSS) or proficient mismatch repair (pMMR) are refractory to immunotherapeutic strategies. The current research focusses on the combined treatment strategies for identification and optimization in order to improve the efficacy of immunotherapy among patients with microsatellite stability (MSS), who account for the majority of metastatic colorectal cancer (mCRC) cases. mCRC patients harboring MSS and the BRAF^V600E mutation show a worse prognosis and barely benefit from immunotherapy. In this report, we discuss the case of a mCRC patient with MSS and BRAF^V600E mutation, who exhibited significant response to the combined treatment with nivolumab and bevacizumab, and has been exhibiting a progression-free survival (PFS) of more than 17 months. Our findings indicate that combined anti-angiogenic therapy can improve the efficacy of immunotherapy, which results in the prolong survival of the patient. This is a case report on MSS and BRAF^V600E colorectal cancer which presents with a response to immunotherapy and anti-angiogenic therapy.

SUBMITTER: Fang C

PROVIDER: S-EPMC8112237 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Metastatic Colorectal Cancer Patient With Microsatellite Stability and BRAF<sup>V600E</sup> Mutation Showed a Complete Metabolic Response to PD-1 Blockade and Bevacizumab: A Case Report.

Fang Chongkai C Lin Jietao J Zhang Tao T Luo Jiajun J Nie Duorui D Li Meng M Hu Xue X Zheng Yating Y Huang Xuewu X Xiao Zhiwei Z

Frontiers in oncology 20210427

A vast majority of colorectal cancer (CRC) patients with microsatellite stability (MSS) or proficient mismatch repair (pMMR) are refractory to immunotherapeutic strategies. The current research focusses on the combined treatment strategies for identification and optimization in order to improve the efficacy of immunotherapy among patients with microsatellite stability (MSS), who account for the majority of metastatic colorectal cancer (mCRC) cases. mCRC patients harboring MSS and the <i>BRAF<sup ...[more]

PMID: 33987088

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Project description:BackgroundB-Raf proto-oncogene, serine/threonine kinase (BRAF)V600E-mutant microsatellite stable (MSS) colorectal cancer (CRC) constitutes a distinct CRC subgroup, traditionally perceived as minimally responsive to standard therapies. Recent clinical attempts, such as BRAF inhibitors (BRAFi) monotherapy and combining BRAFi with other inhibitors, have yielded unsatisfactory efficacy. This study aims to identify a novel therapeutic strategy for this challenging subgroup.MethodsWe first performed a large-scale drug screening using patient-derived organoid models and cell lines to pinpoint potential therapies. Subsequently, we investigated the synergistic effects of identified effective inhibitors and probed their cooperative mechanisms. Concurrently, we explored the immune characteristics of BRAFV600E MSS CRC using RNA sequencing and multiplex immunohistochemistry. Finally, we established a CT26 BRAFV637E mouse cell line and validated the efficacy of combining these inhibitors and programmed death 1 (PD-1) blockades in immunocompetent mice.ResultsDrug screening identified histone deacetylase (HDAC) inhibitor and mitogen-activated protein kinase kinase (MEK) inhibitor as significantly effective against BRAFV600E MSS CRC. Further research revealed that these two inhibitors have superior synergistic effects by comprehensively inhibiting the activation of the epidermal growth factor receptor, mitogen-activated protein kinase, and phosphoinositide 3-kinase-protein kinase B pathways and suppressing the key target homeobox C6 (HOXC6). HOXC6, overexpressed in BRAFV600E MSS CRC, regulates the MYC gene and contributes to treatment resistance, tumor growth, and metastasis. Moreover, the combination therapy demonstrated the ability to enhance antitumor immunity by synergistically upregulating the expression of immune activation-related genes, activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes (cGAS/STING) pathway, and diminishing the tumor cells' DNA mismatch repair capacity. Notably, BRAFV600E MSS CRC was identified to exhibit a distinct immune microenvironment with increased PD-1+ cell infiltration and potential responsiveness to immunotherapy. Echoing the above findings, in vivo, HDAC and MEK inhibitors significantly improved PD-1 blockade efficacy, accompanied by increased CD8+ T-cell infiltration.ConclusionsOur findings indicate that combining HDAC inhibitor, MEK inhibitor, and PD-1 blockade is a potential strategy for treating BRAFV600E-mutant MSS CRC, warranting further investigation in clinical settings.

Dataset Information

Metastatic Colorectal Cancer Patient With Microsatellite Stability and BRAF^V600E Mutation Showed a Complete Metabolic Response to PD-1 Blockade and Bevacizumab: A Case Report.

Publications

Metastatic Colorectal Cancer Patient With Microsatellite Stability and BRAF<sup>V600E</sup> Mutation Showed a Complete Metabolic Response to PD-1 Blockade and Bevacizumab: A Case Report.

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Dataset Information

Metastatic Colorectal Cancer Patient With Microsatellite Stability and BRAFV600E Mutation Showed a Complete Metabolic Response to PD-1 Blockade and Bevacizumab: A Case Report.

Publications

Metastatic Colorectal Cancer Patient With Microsatellite Stability and BRAF<sup>V600E</sup> Mutation Showed a Complete Metabolic Response to PD-1 Blockade and Bevacizumab: A Case Report.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Metastatic Colorectal Cancer Patient With Microsatellite Stability and BRAF^V600E Mutation Showed a Complete Metabolic Response to PD-1 Blockade and Bevacizumab: A Case Report.