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Withdrawal of MEK1/2 inhibitor reverses acquired resistance driven by BRAF amplification but drives EMT and chemoresistance in cells with amplified KRAS

ABSTRACT: Withdrawal of MEK1/2 inhibitor reverses acquired resistance driven by BRAF amplification but drives EMT and chemoresistance in cells with amplified KRAS

PROVIDER: PRJNA495324 | ENA |

REPOSITORIES: ENA

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Withdrawal of MEK1/2 inhibitor reverses acquired resistance driven by BRAF amplification but drives EMT and chemoresistance in cells with amplified KRAS

Project description:Acquired resistance to MEK1/2 inhibitors can arise through amplification of BRAFV600E or KRASG13D to reinstate ERK1/2 signalling. Here we show that BRAFV600E amplification and selumetinib resistance are fully reversible following drug withdrawal. Resistant cells with BRAFV600E amplification become addicted to selumetinib to maintain a precise level of ERK1/2 signalling (2-3% of total ERK1/2 active, here quantified by mass spectrometry), that is optimal for cell survival and proliferation. The magnitude of ERK1/2 activation following selumetinib withdrawal (~20% active) drives a p57KIP2-dependent G1 cell cycle arrest and senescence or expression of NOXA and cell death, which selects against those cells with amplified BRAFV600E. ERK1/2-dependent p57KIP2 expression is required for loss of BRAFV600E amplification and determines the rate of reversal of selumetinib resistance. Furthermore, growth of selumetinib-resistant cells with BRAFV600E amplification as tumour xenografts is inhibited in mice that do not receive selumetinib. Thus, BRAFV600E amplification confers a selective disadvantage during drug withdrawal, providing a rationale for intermittent dosing to forestall resistance. In striking contrast, selumetinib resistance driven by KRASG13D amplification is not reversible. In these cells ERK1/2 reactivation does not inhibit proliferation but drives a ZEB1-dependent epithelial-to-mesenchymal transition that increases cell motility and promotes resistance to traditional chemotherapy agents arguing strongly against the use of ‘drug holidays’ in cases of KRASG13D amplification.

2019-03-11 | GSE120993 | GEO

MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance.

Project description:Acquired resistance to MEK1/2 inhibitors (MEKi) arises through amplification of BRAFV600E or KRASG13D to reinstate ERK1/2 signalling. Here we show that BRAFV600E amplification and MEKi resistance are reversible following drug withdrawal. Cells with BRAFV600E amplification are addicted to MEKi to maintain a precise level of ERK1/2 signalling that is optimal for cell proliferation and survival, and tumour growth in vivo. Robust ERK1/2 activation following MEKi withdrawal drives a p57KIP2-dependent G1 cell cycle arrest and senescence or expression of NOXA and cell death, selecting against those cells with amplified BRAFV600E. p57KIP2 expression is required for loss of BRAFV600E amplification and reversal of MEKi resistance. Thus, BRAFV600E amplification confers a selective disadvantage during drug withdrawal, validating intermittent dosing to forestall resistance. In contrast, resistance driven by KRASG13D amplification is not reversible; rather ERK1/2 hyperactivation drives ZEB1-dependent epithelial-to-mesenchymal transition and chemoresistance, arguing strongly against the use of drug holidays in cases of KRASG13D amplification.

| S-EPMC6497655 | biostudies-literature

RNA-seq analysis of withdrawal of miR-155 hyperexpression in miR-155-addicted tumors

2015-01-30 | GSE61851 | GEO

RNA-seq analysis of withdrawal of miR-155 hyperexpression in miR-155-addicted tumors

Project description:Overexpression of miR-155 in hematological tissue leads to the onset of lymphoma, and Tet-off shutdown of this overexpression reverses the disease phenotype in mir-155LSLtTA mice. This study compares the gene expression profiles of tumors with miR-155 overexpression and withdrawal. Examination of mRNA from 2 conditions: miR-155 overexpressing tumors and miR-155 overexpressing tumors from mice exposed to doxycycline (DOX) for 16hrs prior to harvest; samples in triplicate; tumors generated in flanks of nude mice by subcutaneous injection of splenic cells from diseased mir-155LSLtTA mice.

2015-01-30 | E-GEOD-61851 | biostudies-arrayexpress

Mutant KRAS/BRAF Reprograms the Enhancer Landscape via GATA1 to Drive Chemoresistance

Project description:Despite advances in the detection and management of colorectal cancers, resistance to anti-cancer therapies remains a significant challenge. Activating mutations in KRAS and BRAF are frequently observed in colorectal cancers and have been associated with aggressive tumors and poor survival after chemotherapy. In the present study, we demonstrate that mutations in KRAS/BRAF alter the enhancer landscape of tumor cells, which leads to the resistance of the cornerstone colorectal cancer chemotherapeutic agent 5-fluorouracil (5-FU) through activation of transcription factor GATA1. Targeted inhibition of GATA1 reverses epigenetic changes in KRAS mutant cells and restores sensitivity to 5-FU. These results indicate a novel therapeutic opportunity for tailoring individualized therapy in human colorectal cancer.

2019-10-01 | GSE115400 | GEO

Chemoresistance in PAAD

Project description:Chemoresistance in PAAD using a small sgRNA library

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Gene expression changes upon drug withdrawal

Project description:Gene expression changes upon drug withdrawal

| PRJNA386477 | ENA

CXMS BS3 Ras/BRAF/MEK/1433 complex

Project description:RAF-family kinases are activated by recruitment to the plasma membrane by GTP-bound RAS, where they initiate signaling through the MAP kinase cascade. Here we crosslinked (BS3), digested (trypsin), and analyzed via LC-MS/MS KRAS (human, residues 1-169) bound to intact BRAF (human) in an autoinhibited state with MEK1 (human, ) and a 14-3-3 (SF9) dimer . Analysis of this KRAS/BRAF/MEK1/14-3-3 complex reveals both interprotein and intraprotein crosslinks.

2023-10-24 | PXD042584 | Pride

Mutant KRAS/BRAF Reprograms the Enhancer Landscape via GATA1 to Drive Chemoresistance

Project description:Mutant KRAS/BRAF Reprograms the Enhancer Landscape via GATA1 to Drive Chemoresistance

| PRJNA474834 | ENA

An alternatively spliced p62 isoform promotes breast cancer chemoresistance

Project description:Chemoresistance remains a major obstacle to the successful treatment of breast cancer. Especially, more than 80% of cases cannot achieve pathological complete response (pCR) in patients who received neoadjuvant chemotherapy (NAC). Understanding the mechanisms involved in chemoresistance can guide the development of efficient therapies in patients with breast cancer. Herein, we identified a novel p62 isoform with a short 3′UTR (p62-SU, 662-nt) that is associated with chemoresistance by RNA-sequence and verified by qRT-PCR, 3′RACE, and northern blot in breast cancer cells and tissue specimens. Furthermore, enforced expression of p62-SU dramatically promoted the ability of proliferation, migration, invasion, and chemoresistance compared with p62 isoform with a long/full-length 3′UTR (p62-LU, 1485-nt) in vivo and in vitro. Mechanistically, we revealed that CPSF1 could regulate the 3′UTR shorting of p62 by alternative polyadenylation and then enhanced chemoresistance in breast cancer cells. In addition, we found that p62-SU escaped the repression of miR-124-3p and promoted the ability of p62-SU to produce more protein and, subsequently, p62-dependent chemoresistance. Together, our data suggest the p62-SU, generated by CPSF1, plays an essential role in the regulation of breast cancer chemoresistance through CPSF1-p62-miR-124-3p signaling.

2022-03-06 | GSE197894 | GEO

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