Metastatic melanoma cells commonly acquire resistance to BRAF V600E inhibitors (BRAFi). In this study, we identified serine biosynthesis as a critical mechanism of resistance. Proteomic assays revealed differential protein expression of serine biosynthetic enzymes PHGDH, PSPH, and PSAT1 following vemurafenib (BRAFi) treatment in sensitive versus acquired resistant melanoma cells. Ablation of PHGDH via siRNA sensitized acquired resistant cells to vemurafenib. Inhibiting the folate cycle, directly downstream of serine synthesis, with methotrexate also displayed similar sensitization. Using the DNA-damaging drug gemcitabine, we show that gemcitabine pretreatment sensitized resistant melanoma cells to BRAFis vemurafenib and dabrafenib. We extended our findings to BRAF WT tumor cell lines that are intrinsically resistant to vemurafenib and dabrafenib. Pretreatment of pancreatic cancer and non-small cell lung cancer cell lines with sublethal doses of 50 and 5 nmol/L of gemcitabine, respectively, enhanced killing by both vemurafenib and dabrafenib. The novel aspects of this study are the direct identification of serine biosynthesis as a critical mechanism of BRAF V600E inhibitor resistance and the first successful example of using gemcitabine + BRAFis in combination to kill previously drug-resistant cancer cells, creating the translational potential of pretreatment with gemcitabine prior to BRAFi treatment of tumor cells to reverse resistance within the mutational profile and the WT. Mol Cancer Ther; 16(8); 1596-609. ©2017 AACR.
©2017 American Association for Cancer Research.
p53 Reactivation by PRIMA-1(Met) (APR-246) Sensitises (V600E/K)BRAF Melanoma to Vemurafenib
M Krayem et al.
Eur J Cancer 55, 98-110.
Intrinsic and acquired resistance of metastatic melanoma to (V600E/K)BRAF and/or MEK inhibitors, which is often caused by activation of the PI3K/AKT survival pathway, rep …
Inhibition of Mutant BRAF Splice Variant Signaling by Next-Generation, Selective RAF Inhibitors
KJ Basile et al.
Pigment Cell Melanoma Res 27 (3), 479-84.
Vemurafenib and dabrafenib block MEK-ERK1/2 signaling and cause tumor regression in the majority of advanced-stage BRAF(V600E) melanoma patients; however, acquired resist …
Targeting the PI3K/AKT/mTOR Pathway Overcomes the Stimulating Effect of Dabrafenib on the Invasive Behavior of Melanoma Cells With Acquired Resistance to the BRAF Inhibitor
S Caporali et al.
Int J Oncol 49 (3), 1164-74.
BRAF inhibitors (BRAFi) have proven clinical benefits in patients with BRAF-mutant melanoma. However, acquired resistance eventually arises. The effects of BRAFi on melan …
Dabrafenib Therapy for Advanced Melanoma
VA Trinh et al.
Ann Pharmacother 48 (4), 519-29.
Dabrafenib joins vemurafenib to confirm the superior clinical outcome of the BRAF inhibitors when compared with dacarbazine in patients with BRAF(V600E)-positive advanced …
Overcoming Resistance to BRAF Inhibition in BRAF-mutated Metastatic Melanoma
F Spagnolo et al.
Oncotarget 5 (21), 10206-21.
Almost 50% of metastatic melanoma patients harbor a BRAF(V600) mutation and the introduction of BRAF inhibitors has improved their treatment options. BRAF inhibitors vemu …
PubMed Central articles
Metabolic Imaging Using Hyperpolarized 13 C-pyruvate to Assess Sensitivity to the B-Raf Inhibitor Vemurafenib in Melanoma Cells and Xenografts
S Acciardo et al.
J Cell Mol Med 24 (2), 1934-1944.
Nearly all melanoma patients with a BRAF-activating mutation will develop resistance after an initial clinical benefit from BRAF inhibition (BRAFi). The aim of this work …
Increased Inflammatory Lipid Metabolism and Anaplerotic Mitochondrial Activation Follow Acquired Resistance to Vemurafenib in BRAF-mutant Melanoma Cells
T Delgado-Goñi et al.
Br J Cancer 122 (1), 72-81.
Altogether, our data highlight heterogeneity in metabolic adaptations during acquired resistance to vemurafenib in BRAF-mutant melanoma, potentially uncovering key clinic …
Phosphoserine Phosphatase Promotes Lung Cancer Progression Through the Dephosphorylation of IRS-1 and a Noncanonical L-Serine-Independent Pathway
SM Park et al.
Mol Cells 42 (8), 604-616.
Phosphoserine phosphatase (PSPH) is one of the key enzymes of the L-serine synthesis pathway. PSPH is reported to affect the progression and survival of several cancers i …
Mechanisms of Resistance to a PI3K Inhibitor in Gastrointestinal Stromal Tumors: An omic Approach to Identify Novel Druggable Targets
G Ravegnini et al.
Cancer Manag Res 11, 6229-6244.
Background: Gastrointestinal stromal tumors (GISTs) represent a worldwide paradigm of target therapy. The introduction of tyrosine kinase inhibitors has deeply cha …
Diverse Mechanisms of BRAF Inhibitor Resistance in Melanoma Identified in Clinical and Preclinical Studies
SA Luebker et al.
Front Oncol 9, 268.
BRAF inhibitor therapy may provide profound initial tumor regression in metastatic melanoma with BRAF V600 mutations, but treatment resistance often leads to disease prog …
LinkOut - more resources
Full Text Sources