scholarly journals In Vitro Drug Sensitivity-Gene Expression Correlations Involve a Tissue of Origin Dependency

2006 ◽  
Vol 47 (1) ◽  
pp. 239-248 ◽  
Author(s):  
C. R. Andersson ◽  
M. Fryknäs ◽  
L. Rickardson ◽  
R. Larsson ◽  
A. Isaksson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Sensitivity ◽  
Tissue Of Origin ◽  
Sensitivity Gene

scholarly journals In vitro Drug Sensitivity-Gene Expression Correlations Involve a Tissue of Origin Dependency.

ChemInform ◽  
2007 ◽  
Vol 38 (15) ◽  
Author(s):  
C. R. Andersson ◽  
M. Fryknaes ◽  
L. Rickardson ◽  
R. Larsson ◽  
A. Isaksson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Sensitivity ◽  
Tissue Of Origin ◽  
Sensitivity Gene

Connecting gene expression subtypes of colorectal cancer (CRC) with cell lines and drug resistance.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14544-e14544
Author(s):  
Eva Budinska ◽  
Jenny Wilding ◽  
Vlad Calin Popovici ◽  
Edoardo Missiaglia ◽  
Arnaud Roth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Line ◽  
Clinical Significance ◽  
Cell Lines ◽  
Drug Response ◽  
Drug Sensitivity ◽  
Expression Profiles ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis

e14544 Background: We identified CRC gene expression subtypes (ASCO 2012, #3511), which associate with established parameters of outcome as well as relevant biological motifs. We now substantiate their biological and potentially clinical significance by linking them with cell line data and drug sensitivity, primarily attempting to identify models for the poor prognosis subtypes Mesenchymal and CIMP-H like (characterized by EMT/stroma and immune-associated gene modules, respectively). Methods: We analyzed gene expression profiles of 35 publicly available cell lines with sensitivity data for 82 drug compounds, and our 94 cell lines with data on sensitivity for 7 compounds and colony morphology. As in vitro, stromal and immune-associated genes loose their relevance, we trained a new classifier based on genes expressed in both systems, which identifies the subtypes in both tissue and cell cultures. Cell line subtypes were validated by comparing their enrichment for molecular markers with that of our CRC subtypes. Drug sensitivity was assessed by linking original subtypes with 92 drug response signatures (MsigDB) via gene set enrichment analysis, and by screening drug sensitivity of cell line panels against our subtypes (Kruskal-Wallis test). Results: Of the cell lines 70% could be assigned to a subtype with a probability as high as 0.95. The cell line subtypes were significantly associated with their KRAS, BRAF and MSI status and corresponded to our CRC subtypes. Interestingly, the cell lines which in matrigel created a network of undifferentiated cells were assigned to the Mesenchymal subtype. Drug response studies revealed potential sensitivity of subtypes to multiple compounds, in addition to what could be predicted based on their mutational profile (e.g. sensitivity of the CIMP-H subtype to Dasatinib, p<0.01). Conclusions: Our data support the biological and potentially clinical significance of the CRC subtypes in their association with cell line models, including results of drug sensitivity analysis. Our subtypes might not only have prognostic value but might also be predictive for response to drugs. Subtyping cell lines further substantiates their significance as relevant model for functional studies.

scholarly journals Dasatinib Inhibits FLT3/ITD and PTPN11mutated Acute Myeloid Leukemia Cells Overexpressing SRC Tyrosine Kinases

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1451-1451
Author(s):  
Sigal Tavor ◽  
Tali Shalit ◽  
Noa Chapal Ilani ◽  
Yoni Moskovitz ◽  
Nir Livnat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Drug Sensitivity ◽  
Kinase Inhibitors ◽  
Advisory Committees ◽  
Acute Myeloid

Background: Recent advances in acute myeloid leukemia(AML) targeted therapy improve overall survival. While these targeted therapies can achieve prolonged remissions, most patients will eventually relapseunder therapy. Our recent studies suggest that relapse most often originates from several sub-clones of leukemic stem cells (LSCs), present before therapy initiation, and selected due to several resistance mechanisms. Eradication of these LSCs during treatment induction /remission could thus potentially prevent relapse. The overall goal of the current study was to identify drugs which can be safely administrated to patients at diagnosis and that will target LSCs. Since simultaneously testing multiple drugs in vivo is not feasible, we used an in vitrohigh throughput drug sensitivity assay to identify new targets in primary AML samples. Methods: Drug sensitivity and resistance testing (DSRT) was assessed in vitro (N=46 compounds) on primary AML samples from patients in complete remission (N=29). We performed whole exome sequencing and RNAseq on samples to identify correlations between molecular attributes and in vitro DSRT. Results:Unsupervised hierarchical clustering analysis of in vitro DSRT, measured by IC50, identified a subgroup of primary AML samples sensitive to various tyrosine kinase inhibitors (TKIs). In this subgroup, 52% (9/17) of AML samples displayed sensitivity to dasatinib (defined as a 10-fold decrease in IC50 compared to resistant samples). Dasatinib has broad TKI activity, and is safely administered in the treatment of leukemia. We therefore focused our analysis on predicting AML response to dasatinib, validating our results on the Beat AML cohort. Enrichment analysis of mutational variants in dasatinib-sensitive and resistant primary AML samples identified enrichment of FLT3/ITD (p=0.05) and PTPN11(p=0.05) mutations among dasatinib responders. Samples resistant to dasatinib were enriched with TP53 mutations (p=0.01). No global gene expression changes were observed between dasatinib-sensitive and resistant samples in our cohort, nor in the Beat AML cohort. Following this, we tested the differential expression of specific dasatinib-targeted genes between dasatinib-responding and resistant samples. No significant differences were identified. However, unsupervised hierarchical clustering of dasatinib targeted genes expression in our study and in the Beat AML cohort identified a subgroup of AML samples (enriched in dasatinib responders) that demonstrated overexpression of three SRC family tyrosine kinases:FGR, HCK and LYN as well as PTK6, CSK, GAK and EPHB2. Analysis of the PTPN11 mutant samples revealed that the IC50 for dasatinib in 23 carriers of the mutant PTPN11 was significantly lower compared to the IC50 of PTPN11 wild type samples (p=0.005). LYN was also upregulated (p&lt;0.001) in the mutant samples. We therefore hypothesized that gene expression of dasatinib-targeted genes could be used as a predictive biomarker of dasatinib response among FLT3/ITD carriers. We found that among FLT3/ITD AML carriers in the Beat AML cohort LYN, HCK, CSK and EPHB2 were significantly over-expressed in the dasatinib responding samples (N=27) as compared to the dasatinib resistant samples (N=35). To predict response to dasatinib among FLT3/ITD carriers we used a decision tree classifier based on the expression levels of these four genes. Our prediction model yielded a sensitivity of 74% and specificity of 83% for differentiating dasatinib responders from non-responders with an AUC of 0.84. Based on our findings, we selected FLT3/ITD AML samples and injected them to NSG-SGM3 mice. We found that in a subset of these samples, dasatinib significantly inhibited LSCs engraftment. This subset of FLT3/ITD AML samples expressed higher levels of LYN, HCK,FGR and SRC as compared to the FLT3/ITD samples that were not sensitive to dasatinib therapy in vivo. In summary, we identified a subgroup of AML patients sensitive to dasatinib, based on mutational and expression profiles. Dasatinib has anti-leukemic effects on both blasts and LSCs. Further clinical studies are needed to demonstrate whether selection of tyrosine kinase inhibitors, based on specific biomarkers, could indeed prevent relapse. Disclosures Tavor: Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS companies: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Clinical drug response can be predicted using baseline gene expression levels and in vitro drug sensitivity in cell lines

2014 ◽  
Vol 15 (3) ◽  
pp. R47 ◽  
Author(s):  
Paul Geeleher ◽  
Nancy J Cox ◽  
R Huang
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Drug Response ◽  
Drug Sensitivity ◽  
Expression Levels ◽  
Clinical Drug ◽  
Gene Expression Levels

scholarly journals Predicting chemosensitivity using drug perturbed gene dynamics

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Joshua D. Mannheimer ◽  
Ashok Prasad ◽  
Daniel L. Gustafson
Keyword(s):  
Gene Expression ◽  
Cell Line ◽  
Computational Methods ◽  
Predictive Models ◽  
Drug Response ◽  
Drug Sensitivity ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Gene Signatures

Abstract Background One of the current directions of precision medicine is the use of computational methods to aid in the diagnosis, prognosis, and treatment of disease based on data driven approaches. For instance, in oncology, there has been a particular focus on development of algorithms and biomarkers that can be used for pre-clinical and clinical applications. In particular large-scale omics-based models to predict drug sensitivity in in vitro cancer cell line panels have been used to explore the utility and aid in the development of these models as clinical tools. Additionally, a number of web-based interfaces have been constructed for researchers to explore the potential of drug perturbed gene expression as biomarkers including the NCI Transcriptional Pharmacodynamic Workbench. In this paper we explore the influence of drug perturbed gene dynamics of the NCI Transcriptional Pharmacodynamics Workbench in computational models to predict in vitro drug sensitivity for 15 drugs on the NCI60 cell line panel. Results This work presents three main findings. First, our models show that gene expression profiles that capture changes in gene expression after 24 h of exposure to a high concentration of drug generates the most accurate predictive models compared to the expression profiles under different dosing conditions. Second, signatures of 100 genes are developed for different gene expression profiles; furthermore, when the gene signatures are applied across gene expression profiles model performance is substantially decreased when gene signatures developed using changes in gene expression are applied to non-drugged gene expression. Lastly, we show that the gene interaction networks developed on these signatures show different network topologies and can be used to inform selection of cancer relevant genes. Conclusion Our models suggest that perturbed gene signatures are predictive of drug response, but cannot be applied to predict drug response using unperturbed gene expression. Furthermore, additional drug perturbed gene expression measurements in in vitro cell lines could generate more predictive models; but, more importantly be used in conjunction with computational methods to discover important drug disease relationships.

COXEN prediction of antineoplastic drug sensitivity in bladder cancer patients.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 365-365
Author(s):  
Shalin Kothari ◽  
Daniel Gustafson ◽  
Keith Killian ◽  
James Costello ◽  
Daniel C. Edelman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Gene Expression Data ◽  
Drug Sensitivity ◽  
Model Building ◽  
Response To Therapy ◽  
Antineoplastic Drug ◽  
In Vitro Assays ◽  
Expression Data

365 Background: COXEN (Co-eXpression ExtrapolatioN) uses molecular profiles as a “rosetta stone” for translating drug sensitivities of one set of cancers into predictions for another completely independent set of cell lines or human tumors. The ability of COXEN to predict drug effectiveness in pts using tumor samples from in vitro assays is unique. Methods: We tested the predictive value of COXEN for standard chemotherapies in a cohort of bladder cancer pts. Total RNA was extracted from formalin fixed paraffin embedded (FFPE) tissue and converted to cDNA, amplified with Ovation FFPE WTA, and hybridized to a GeneChip Human Genome U133 Plus 2.0 array. Using gene expression data from 278 independent bladder tumors, COXEN scores were generated using bioinformatics models originally built using the NCI-60 cell line panel and a model building algorithm (MiPP). Gene expression data was processed to score 76 FDA approved antineoplastic drugs. Results: A total of 24 samples were tested (15 tumors with 1 sample and 9 tumors with 2 biological replicas (2 samples from the same tumor)) from 15 pts who received chemotherapy (median age 64 (41-74); 73% male; with muscle invasive bladder cancer (MIBC) (12/15, 80%) or metastatic bladder cancer (mBC) (3/15, 20%)). Response to therapy was confirmed by pathologic response in MIBC pts and radiologic response in mBC pts. Chemotherapies evaluated included: methotrexate/vinblastine/doxorubicin/cisplatin; gemcitabine/cisplatin; gemcitabine/carboplatin; and cisplatin/etoposide. COXEN accurately predicted antineoplastic drug sensitivity in 11/15 (73%) pts (75% MIBC and 67% mBC), of which 7/11 pts had 2 biological samples. However, only 3/7 (43%) biological replicas confirmed COXEN prediction. COXEN accurately predicted drug sensitivity in 9/10 (90%) pts with response and 2/5 (40%) pts with resistance to therapy. Conclusions: COXEN did well in predicting antineoplastic drug response for the majority of bladder cancer pts in this cohort. However, predictions from 2 samples within the same tumor were not always consistent, likely due to the expected tumor heterogeneity found in bladder cancer tumors. A prospective clinical trial in patients with mBC using COXEN to select next best therapy is in development.

scholarly journals Identification of Novel Therapeutic Strategies for NUP98-NSD1-Positive AML By Drug Sensitivity Profiling

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2160-2160
Author(s):  
Jarno Kivioja ◽  
Mika Kontro ◽  
Angeliki Thanasopoulou ◽  
Muntasir Mamun Majumder ◽  
Bhagwan Yadav ◽  
...  
Keyword(s):  
Gene Expression ◽  
Research Funding ◽  
Drug Response ◽  
Drug Sensitivity ◽  
Lentiviral Vector ◽  
Potential Candidate ◽  
Flt3 Inhibitors ◽  
Cells Cultured

Abstract Background The t(5;11)(q35;p15.5) translocation resulting in fusion of the nucleoporin NUP98 and methyltransferase NSD1 (NUP98-NSD1) genes is a recurrent aberration observed in pediatric and adult AML. The NUP98-NSD1 fusion often co-occurs with the FLT3-ITD mutation and characterizes a group of cytogenetically normal AML patients with very poor prognosis. Despite advances in the understanding of the biology of NUP98-NSD1-positive AML, its therapeutic success rate has remained low. We aimed to identify novel candidate drugs for NUP98-NSD1-positive AML by testing primary patient cells and in vitro cell models with a high-throughput drug sensitivity platform. Methods Leukemic blasts were Ficoll separated from bone marrow (BM) aspirates of an AML patient positive for t(5;11)(q35;p15.5) and FLT3-ITD. RNA extracted from primary cells was used for RNA sequencing and gene expression analysis. NUP98-NSD1 cDNA was amplified from primary cell RNA and expressed from a lentiviral vector (LeGO-iCer2) also encoding the cerulean fluorescent marker. The NUP98-NSD1/LeGo-iCer2 and empty LeGo-iCer2 viruses were used to establish stably expressing Ba/F3 cell lines. Primary murine (BALB/c) BM cells were transduced with NUP98-NSD1 and FLT3-ITD retroviruses alone or in combination (NNF) in vitro (“preleukemic”) or passaged in vivo (“leukemic”) as previously described (Thanasopoulou et al, 2014). For screening, 309 small molecule inhibitors including FDA/EMA-approved and investigational oncology drugs were plated on 384-well plates in a 10,000-fold concentration range. Cells were dispensed on the pre-drugged plates and incubated at 37°C for 72h, and then cell viability measured using the CellTiter-Glo® luminescent assay. Drug response curves were generated and a drug sensitivity score determined (Yadav et al, 2014). Select drug sensitivity was calculated for each drug by comparing results between primary leukemic and healthy donor BM cells or between the cell constructs and empty vector transduced controls cells. Results Primary patient cells and murine BM cells expressing FLT3-ITD alone or in combination with NUP98-NSD1 were selectively sensitive to specific FLT3 inhibitors (e.g. quizartinib, sorafenib and lestaurtinib), and broad-spectrum receptor tyrosine kinase inhibitors targeting FLT3-ITD (e.g. cabozantinib, crenolanib, foretinib, midostaurin, MGCD-265 and ponatinib). Furthermore, these cells were highly sensitive to checkpoint kinase 1/2- inhibitor AZD7762. The primary murine cells expressing both NUP98-NSD1 and FLT3-ITD showed higher sensitivity to all of the above-mentioned drugs compared to cells expressing either of the events alone indicating functional synergy. A very distinct drug response pattern was observed in the leukemic NNF cells cultured in vivo compared to the same cells cultured in vitro suggesting that microenvironment may also affect the observed drug responses. Interestingly, the preleukemic murine cells expressing NUP98-NSD1 with or without FLT3-ITD as well as the primary patient cells showed extreme vulnerability to BCL2/BCL-xL inhibitor navitoclax. Furthermore, primary murine cells expressing NUP98-NSD1 alone showed high select sensitivity to JAK-inhibitors ruxolitinib, BMS-911543, AZD1480 and tofacitinib indicating the fusion may stimulate JAK/STAT-signaling. Similar sensitivity was also observed in the Ba/F3-cells expressing NUP98-NSD1. In support of these findings, gene expression analyses showed high expression of anti-apoptotic factors BCL2, BCL-xL and MCL1 in the patient cells. MCL1 is regulated by STAT3 while BCL-xL is regulated by STAT5, which were also highly expressed. Conclusions In summary, we have observed an enhanced response to specific and non-specific FLT3 inhibitors in cells expressing NUP98-NSD1 and FLT3-ITD together compared to cells expressing either of the two alone. This coincides with previous findings that functional co-operation between NUP98-NSD1 and FLT3-ITD is important in AML (Thanasopoulou et al, 2014). We have seen high in-vitro-in-vivo correlation between primary patient cells and murine cells expressing NUP98-NSD1 and FLT3-ITD. Moreover, we have identified potential candidate compounds targeting oncogenic signaling activated by these two events. These data form a basis for clinical evaluation of candidate compounds for NUP98-NSD1-positive AML. Disclosures Porkka: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Heckman:Celgene: Research Funding.

Targeted Inhibition of the MLL Transcriptional Complex By Proteosome Inhibitors Elicits a High Response Rate in Relapsed/Refractory MLL Rearranged Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 972-972 ◽  
Author(s):  
Cary Koss ◽  
Stephanie Nance ◽  
Michele Connelly ◽  
Jing Ma ◽  
Anang Shelat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Clinical Trials ◽  
Fusion Protein ◽  
Drug Sensitivity ◽  
Response Rate ◽  
Epigenetic Mark ◽  
Pediatric Leukemia ◽  
Nsg Mice

Abstract Infants with MLL rearranged (MLLr) acute lymphoblastic leukemia (ALL) have a poor prognosis, with an event free survival of only 23-44%. Whole genome sequencing (WGS) of this subtype has revealed a paucity of cooperating mutations, with an average of 2.2 somatic single nucleotide variations and/or insertions/deletions per case. Despite recent progress in defining the epigenetic alterations that result from the expression of the MLL fusion protein, these insights have only recently begun to be extrapolated into the development of new therapeutic approaches whose benefits have yet to be defined. Thus, there remains an urgent need for the development of alternative approaches to improve outcomes in these patients. To identify compounds that are active in MLLr disease, we established in vitro and in vivo assays to evaluate drug sensitivity of primary infant ALL patient samples. 15 infant MLLr leukemia samples that have previously undergone WGS were xenografted into NOD/SCID/IL2Rγnull (NSG) mice. All samples engrafted and expanded in NSG mice, leading to overt leukemia with a latency of 49 to 276 days. Purification of leukemic blasts from a single moribund mouse yielded on average 108 cells, providing sufficient material to screen large numbers of compounds. In vitro conditions were defined that support growth in 40% of the patient specimens, allowing for a more accurate determination of drug sensitivity. Growth in vitro was associated with early onset of disease in NSG xenografts and younger age at presentation, allowing us to evaluate patient samples that represent aggressive high risk disease. Using this system, we tested bortezomib in addition to 28 other drugs, including standard ALL therapeutic agents as well as targeted kinase inhibitors and inhibitors of epigenetic marks. Three classes of agents were active in this system: anthracyclines, histone deacetylase inhibitors (HDACi), and the proteasome inhibitor bortezomib. In contrast to anthracyclines and HDACi, where IC50 values were on par with those reported in the literature for primary childhood ALL samples, MLLr infant samples required 10-100 fold less bortezomib to induce toxicity. Bortezomib has been shown to mediate responses through several mechanisms, including NFKB inhibition, stabilization of cell cycle regulatory proteins, and induction of apoptosis. Recently, proteasome inhibition has been demonstrated to lead to accumulated MLL fusion protein levels, triggering apoptosis and cell cycle arrest in MLLr cell lines. To determine if NFKB inhibition also plays a role, we evaluated cellular concentrations of the activated NFKB transcription factor, but failed to see decreased levels when MLLr cells were treated with bortezomib. Bortezomib has also been shown to deregulate ubiquitin stores and deplete histone H2B ubiquitination (H2Bub), an epigenetic mark that is linked to histone methylation and expression. Recently, several groups have demonstrated that H2Bub is required for DOT1L activity and HOX gene expression. We therefore evaluated H2Bub levels in bortezomib-treated patient samples and confirmed depletion of this epigenetic mark. Furthermore, patient samples treated with bortezomib downregulated both the MLL gene expression signature and signatures of downstream targets, such as cMYC, demonstrating that the MLL transcriptional program is inhibited in the presence of bortezomib. ChIP-seq is underway to map H2Bub and H3K79 methylation changes genome wide in response to treatment with bortezomib. The HDACi vorinostat and bortezomib have both been evaluated in Phase I and II pediatric leukemia clinical trials. Based on the safety and efficacy from these earlier studies, we treated 6 relapsed/refractory MLLr leukemia patients with a chemotherapy regimen that included mitoxantrone, vorinostat, and bortezomib. 4 patients had a complete response (CR), 1 patient had a partial response (PR) and 1 patient had stable disease for an overall response rate of 5/6 (83%). Clinical trials are in development to assess this combination further for both relapsed MLLr disease as well as newly diagnosed infant ALL. Our data suggests that these three classes of drugs, identified in our laboratory assays, are clinically active thus validating our system. We are now using this platform to proceed with a high throughput drug screen to identify additional compounds for future clinical development. Disclosures Off Label Use: Vorinostat and Bortezomib for the treatment of pediatric leukemia.

scholarly journals Multi-Omics Analysis of the Therapeutic Value of MAL2 Based on Data Mining in Human Cancers

2022 ◽  
Vol 9 ◽  
Author(s):  
Jing Yuan ◽  
Xiaoyan Jiang ◽  
Hua Lan ◽  
Xiaoyu Zhang ◽  
Tianyi Ding ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Cell Lines ◽  
Western Blotting ◽  
Drug Sensitivity ◽  
Qrt Pcr ◽  
Human Cancers ◽  
The Impact

Recent studies have reported that T-cell differentiation protein 2 (MAL2) is an important regulator in cancers. Here, we downloaded data from multiple databases to analyze MAL2 expression and function in pan-cancers, especially in ovarian cancer (OC). Gene Expression Profiling Interactive Analysis (GEPIA) databases was used to examine MAL2 expression in 13 types of cancer. Kaplan–Meier plotter database was used to analyze the overall survival rate of MAL2 in pan-cancers. The Catalog of Somatic Mutations in Cancer (COSMIC), cBioPortal, and UCSC databases were used to examine MAL2 mutation in human cancers. Metascape, STRING, and GeneMANIA websites were used to explore MAL2 function in OC. Furthermore, ggplot2 package and ROC package were performed to analyze hub gene expression and undertake receiver operating characteristic (ROC) analysis. Drug sensitivity of MAL2 in OC was examined by the GSCALite database. In order to verify the results from databases above, real-time quantitative polymerase chain reaction (qRT-PCR) and western blotting were conducted to detect the expression of MAL2 in OC cells. CRISPR/Cas9 system was used to knockout the MAL2 gene in the OC cell lines HO8910 and OVCAR3, using specific guide RNA targeting the exons of MAL2. Then, we performed proliferation, colony formation, migration, and invasion assays to investigate the impact of MAL2 in OC cell lines in vivo and in vitro. Epithelial-mesenchymal transition (EMT)-associated biomarkers were significantly altered in vitro via western blotting and qRT-PCR. Taken together, we observed that MAL2 was remarkably dysregulated in multiple cancers and was related to patient overall survival (OS), mutation, and drug sensitivity. Furthermore, experimental results showed that MAL2 deletion negatively regulated the proliferation, migration, invasion, and EMT of OC, indicating that MAL2 is a novel oncogene that can activate EMT, significantly promote both the proliferation and migration of OC in vitro and in vivo, and provide new clues for treatment strategies.

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