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Case report: Major pathologic response induced by neoadjuvant treatment using BRAF and MEK inhibitors in a patient with stage IIIA lung adenocarcinoma harboring BRAF V600E-mutation.

ABSTRACT: Targeted therapy has achieved great success in advanced non-small lung cancer (NSCLC) with driver genes, and neoadjuvant-targeted therapy is increasingly being investigated. Although neoadjuvant-targeted therapy with EGFR-TKI and ALK-TKI showed good efficacy, there is no report of neoadjuvant-targeted therapy to BRAF V600E mutation on NSCLC so far. Here, we report the first case of a successful neoadjuvant-targeted therapy with BRAF and MEK inhibitors followed by radical surgical excision with major pathologic response (MPR) in a patient with stage IIIA lung adenocarcinoma (LUAD) harboring BRAF V600E mutation. The case informs us that targeted therapy with BRAF and MEK inhibitors could be administrated as a neoadjuvant strategy for selected cases of NSCLC harboring BRAF V600E mutation.

SUBMITTER: Liu C

PROVIDER: S-EPMC9393753 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Case report: Major pathologic response induced by neoadjuvant treatment using BRAF and MEK inhibitors in a patient with stage IIIA lung adenocarcinoma harboring BRAF V600E-mutation.

Liu Chaoyuan C Lu Min M Yang Yang Y Wang Xiang X Ma Fang F Liu Xianling X

Frontiers in oncology 20220808

Targeted therapy has achieved great success in advanced non-small lung cancer (NSCLC) with driver genes, and neoadjuvant-targeted therapy is increasingly being investigated. Although neoadjuvant-targeted therapy with EGFR-TKI and ALK-TKI showed good efficacy, there is no report of neoadjuvant-targeted therapy to BRAF V600E mutation on NSCLC so far. Here, we report the first case of a successful neoadjuvant-targeted therapy with BRAF and MEK inhibitors followed by radical surgical excision with m ...[more]

PMID: 36003777

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Project description:Background Main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF- mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to define in this context the specific role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit and regarded as an oncogenic driver in several tumor types, including MM. Methods After analyzing the TCGA MM patients’ database to explore both overall survival and molecular signatures as a function of intra-tumor RICTOR levels, we investigated the effects of RICTOR downregulation in BRAF V600E MM cell lines on their response to BRAF/MEKi in vitro. We performed a proteomic screening to identify proteins modulated by changes in RICTOR expression and Seahorse analysis to evaluate the effects of RICTOR depletion on mitochondrial respiration. The combination of BRAFi with drugs targeting proteins and processes emerged in the proteomic screening was carried out on RICTOR-deficient cells in vitro and in a xenograft setting in vivo. Results We found that low RICTOR levels in MM correlate with an overall worse clinical outcome. GSEA of low- RICTOR tumors revealed a gene expression signature suggestive of activation of the mitochondrial Electron Transport Chain (ETC) energy producing pathway. RICTOR-deficient BRAF V600E cells are intrinsically tolerant to BRAFi/MEKi and anticipate the onset of resistance to BRAFi upon prolonged drug exposure. In RICTOR- depleted cells, both mitochondrial respiration and expression of nicotinamide phosphoribosyltransferase (NAMPT) are enhanced, while their pharmacological inhibition restores sensitivity to BRAFi. Conclusions Our work unveils a novel tumor suppressing role for mTORC2 in the responses of BRAF V600E melanoma cells to targeted therapy and identifies the NAMPT-ETC axis as a potential therapeutic vulnerability of low- RICTOR tumors. Importantly, our findings support the concept that the evaluation of intra-tumor RICTOR levels in MM has a prognostic value, and may help predicting the response of patients to targeted therapy.

Dataset Information

Case report: Major pathologic response induced by neoadjuvant treatment using BRAF and MEK inhibitors in a patient with stage IIIA lung adenocarcinoma harboring BRAF V600E-mutation.

Publications

Case report: Major pathologic response induced by neoadjuvant treatment using BRAF and MEK inhibitors in a patient with stage IIIA lung adenocarcinoma harboring BRAF V600E-mutation.

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