Therapeutic Target In Human Cancer Research Articles

HIPK2 directs cell type–specific regulation of STAT3 transcriptional activity in Th17 cell differentiation

SignificanceSTAT3 (signal transducer and activator of transcription 3) is a master transcription factor that organizes cellular responses to cytokines and growth factors and is implicated in inflammatory disorders. STAT3 is a well-recognized therapeutic target for human cancer and inflammatory disorders, but how its function is regulated in a cell type-specific manner has been a major outstanding question. We discovered that Stat3 imposes self-directed regulation through controlling transcription of its own regulator homeodomain-interacting protein kinase 2 (Hipk2) in a T helper 17 (Th17) cell-specific manner. Our validation of the functional importance of the Stat3-Hipk2 axis in Th17 cell development in the pathogenesis of T cell-induced colitis in mice suggests an approach to therapeutically treat inflammatory bowel diseases that currently lack a safe and effective therapy.

DUXAP8: A Promising lncRNA with Carcinogenic Potential in Cancer.

Long non-coding RNAs (lncRNA) have influenced numerous biology processes, which has provoked great interest. Not only that, LncRNA DUXAP8 mediates tumorigenesis by affecting the activity of miRNAs, signaling pathways, and oncogene. The functions of DUXAP8 have been summarized by reading relevant articles on PubMed. lncRNA DUXAP8 acts as an oncogene in most tumors. The abnormal overexpression is associated with the proliferation, invasion, migration, and anti-autophagy of tumors. DUXAP8 exerts promotion on Akt / mTOR signaling pathway, facilitating the occurrence of tumors. Furthermore, DUXAP8 affects the activity of miRNAs and proteins, showing its significant potential as a therapeutic target in human cancers. LncRNA DUXAP8 has been identified as an indispensable therapeutic target of the tumors, providing clinical treatment plans.

LncRNA GACAT3: A Promising Biomarker and Therapeutic Target in Human Cancers.

Long non-coding RNAs (lncRNAs) are a class of functional RNA molecules that do not encode proteins and are composed of more than 200 nucleotides. LncRNAs play important roles in epigenetic and gene expression regulation. The oncogenic lncRNA GACAT3 was recently discovered to be dysregulated in many tumors. Aberrant expression of GACAT3 contributes to clinical characteristics and regulates multiple oncogenic processes. The association of GACAT3 with a variety of tumors makes it a promising biomarker for diagnosis, prognosis, and targeted therapy. In this review, we integrate the current understanding of the pathological features, biological functions, and molecular mechanisms of GACAT3 in cancer. Additionally, we provide insight into the utility of GACAT3 as an effective diagnostic and prognostic marker for specific tumors, which offers novel opportunities for targeted therapeutic intervention.

Prognostic Potential of METTL7B in Glioma

Objective: Methyltransferase-like 7B (METTL7B) is a member of methyltransferase-like family. Little is known about the exact role of METTL7B in cancer. This study aims to investigate the role of METTL7B in gliomas. Methods: The expression of METTL7B in glioma and adjacent normal tissues were examined by using TCGA, Chinese Glioma Genome Atlas (CGGA) database, and clinical tissues. Results: The results showed that METTL7B was highly expressed in glioma. Patients with high levels of METTL7B usually had poor survival in glioma, especially in low-grade glioma (LGG). Data from CGGA showed that METTL7B was an independent risk factor of glioma and can be used to evaluate the survival time of glioma patients. Hypomethylation in the METTL7B CpG islands was lower in LGG, and all the hypomethylated METTL7B islands were correlated with poor LGG survival. Furthermore, METTL7B levels were correlated with high numbers of tumor infiltrated immune cells in glioma, especially in LGG. ). Gene Set Enrichment Analysis found METTL7B was correlated with leukocyte proliferation, T-cell proliferation, peptidase activity, lymphocyte activation, etc. TCGA and CGGA database analysis showed that there were 1,546 and 1,117 genes that had a synergistic effect with METTL7B in glioma, respectively, and there were 372 genes overlapped between the 2 groups, including PD-L1. Data from clinical tissues also showed PD-L1 was highly expressed in glioma tissues and was positively correlated with METTL7B. Conclusion: Our study suggested that METTL7B was a potential prognostic biomarker for glioma and other cancers, and it may act as an oncogenic driver and may be a potential therapeutic target in human cancer, especially in LGG.

Role of SLC39A6 in the development and progression of liver cancer.

Liver cancer is one of the most common malignant solid tumor types worldwide. The solute carrier (SLC)39A family is a main member of the SLC group of membrane transport proteins, which transfer zinc to the cytoplasm when cells are depleted of zinc; thus, it may provide a novel therapeutic target for human cancer. However, the prognostic value of SLC39A genes in patients with liver cancer has remained elusive. Therefore, the present study aimed to explore whether SLC39A family genes are associated with the survival rate of patients with liver cancer and to investigate the role of key genes of the SLC39A family in liver cancer. The mRNA expression of the SLC39A family in liver cancer was obtained from the UALCAN database. Survival curve analysis was performed to investigate the prognostic value of SLC39A family genes in the overall survival of patients with liver cancer. In addition to the bioinformatics analysis, SLC39A6 was knocked down in HepG2 and Hep3B cells to examine the effect on the proliferation, migration and invasion of liver cancer cells. The results suggested that SLC39A6 was significantly upregulated in liver cancer tissues compared with normal liver tissues. High expression of SLC39A6 was significantly associated with poor overall survival of patients with liver cancer. Furthermore, knockdown of SLC39A6 inhibited the proliferation, migration and invasion of liver cancer cells in vitro and in vivo. Collectively, the results of the present study suggested that SLC39A6 may be a promising prognostic biomarker for liver cancer and is associated with the proliferation, migration and invasion of liver cancer.

LINC00885 promotes cervical cancer progression through sponging miR-3150b-3p and upregulating BAZ2A

BackgroundCervical cancer (CC) is one of the most common malignancies affecting female worldwide. Long non-coding RNAs (lncRNAs) are increasingly indicated as crucial participants and promising therapeutic targets in human cancers. The main objective of this study was to explore the functions and mechanism of LINC00885 in CC.MethodsRT-qPCR and western blot were used to detect RNA and protein levels. Functional and mechanism assays were respectively done for the analysis of cell behaviors and molecular interplays.ResultsLong intergenic non-coding RNA 885 (LINC00885) was discovered to be upregulated in CC tissues and cell lines through bioinformatics analysis and RT-qPCR. Overexpression of LINC00885 promoted proliferation and inhibited apoptosis, whereas its silence exerted opposite effects. The cytoplasmic localization of LINC00885 was ascertained and furthermore, LINC00885 competitively bound with miR-3150b-3p to upregulate BAZ2A expression in CC cells. Rescue assays confirmed that LINC00885 regulated CC proliferation and apoptosis through miR-3150b-3p/BAZ2A axis. Finally, we confirmed that LINC00885 aggravated tumor growth through animal experiments.ConclusionsLINC00885 exerted oncogenic function in CC via regulating miR-3150b-3p/BAZ2A axis. These findings suggested LINC00885 might serve as a potential promising therapeutic target for CC patients.

Emerging Role of Cancer-Associated Fibroblasts-Derived Exosomes in Tumorigenesis.

Cancer-associated fibroblasts (CAFs) are the most important component of the stromal cell population in the tumor microenvironment and play an irreplaceable role in oncogenesis and cancer progression. Exosomes, a class of small extracellular vesicles, can transfer biological information (e.g., proteins, nucleic acids, and metabolites as messengers) from secreting cells to target recipient cells, thereby affecting the progression of human diseases, including cancers. Recent studies revealed that CAF-derived exosomes play a crucial part in tumorigenesis, tumor cell proliferation, metastasis, drug resistance, and the immune response. Moreover, aberrant expression of CAF-derived exosomal noncoding RNAs and proteins strongly correlates with clinical pathological characterizations of cancer patients. Gaining deeper insight into the participation of CAF-derived exosomes in tumorigenesis may lead to novel diagnostic biomarkers and therapeutic targets in human cancers.

The Role of TRIP6, ABCC3 and CPS1 Expression in Resistance of Ovarian Cancer to Taxanes.

The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients’ poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.

AMBRA1 attenuates the proliferation of uveal melanoma cells.

Uveal melanoma (UVM) is the most common primary intraocular malignancy in adults with high metastasis rates. D-type cyclins (CCNDs) are central regulators of the cell division cycle and are among the most frequently deregulated therapeutic targets in human cancer. Recently, the E3 ligase adaptor, autophagy and beclin 1 regulator 1 (AMBRA1), was reported to regulate the stability of CCNDs, including CCND1, but its role in UVM has not been demonstrated. AMBRA1 is lowly expressed in UVM cells, and the ablation of AMBRA1 promotes the proliferation of 92.1 and OMM1 cells, whereas ectopically expressing AMBRA1 attenuates the proliferation of UVM cells. Further studies found that AMBRA1 promotes the ubiquitination and degradation of CCND1, and AMBRA1 regulates the proliferation of UVM cells in a CCND1-dependent manner. Thus, this study suggests that AMBRA1 serves as an important tumor suppressor by limiting UVM cell growth.

KCNQ1OT1: An Oncogenic Long Noncoding RNA.

Long noncoding RNAs (lncRNAs) are transcripts greater than 200 nucleotides that do not code for proteins but regulate gene expression. Recent studies indicate that lncRNAs are involved in the modulation of biological functions in human disease. KCNQ1 Opposite Strand/Antisense Transcript 1 (KCNQ1OT1) encodes a lncRNA from the opposite strand of KCNQ1 in the CDKN1C/KCNQ1OT1 cluster that is reported to play a vital role in the development and progression of cancer. KCNQ1OT1 regulates cancer cell proliferation, cell cycle, migration and invasion, metastasis, glucose metabolism, and immune evasion. The aberrant expression of KCNQ1OT1 in cancer patients is associated with poor prognosis and decreased survival. This review summarizes recent literature related to the biological functions and molecular mechanisms of KCNQ1OT1 in various human cancers, including colorectal, bladder, breast, oral, melanoma, osteosarcoma, lung, glioma, ovarian, liver, acute myeloid leukemia, prostate, and gastric. We also discuss the role of KCNQ1OT1 as a promising diagnostic biomarker and a novel therapeutic target in human cancers.

Pan-cancer analysis combined with experiments predicts CTHRC1 as a therapeutic target for human cancers

BackgroundThe function of collagen triple helix repeat containing 1 (CTHRC1) as an oncogene has been reported in a growing number of publications. Bioinformatics methods represent a beneficial approach to examine the mechanism and function of the CTHRC1 gene in the disease process of cancers from a pan-cancer perspective.MethodsIn this study, using the online databases UCSC, NCBI, HPA, TIMER2, Oncomine, GEPIA, UALCAN, cBioPortal, COSMIC, MEXPRESS, STRING, CCLE, LinkedOmics, GTEx, TCGA, CGGA, and SangerBox, we focused on the relationship between CTHRC1 and tumorigenesis, progression, methylation, immunity, and prognosis. qPCR was used to detect CTHRC1 expression in glioma tissues and cell lines.ResultsThe pan-cancer analysis showed that CTHRC1 was overexpressed in most tumors, and a significant correlation was observed between CTHRC1 expression and the prognosis of patients with cancer. CTHRC1 genetic alterations occur in diverse tumors and are associated with tumor progression. Levels of CTHRC1 promoter methylation were decreased in most cancer tissues compared with normal tissues. In addition, CTHRC1 coordinated the activity of ICP genes through diverse signal transduction pathways, was also associated with immune cell infiltration and the tumor microenvironment, and potentially represented a promising immunotherapy target. We identified CTHRC1-related genes across cancers using the GEPIA2 tool. The single-gene GO analysis of CTHRC1 across cancers showed that it was involved in some signaling pathways and biological processes, such as the Wnt signaling pathway, cell migration, and positive regulation of protein binding. The expression and function of CTHRC1 were also further verified in glioma tissues and cell lines.ConclusionsCTHRC1 is overexpressed in various cancer types and functions as an important oncogene that may promote tumorigenesis and development through different mechanisms. CTHRC1 may represent an important therapeutic target for human cancers.

Discovery of EEDi-5273 as an Exceptionally Potent and Orally Efficacious EED Inhibitor Capable of Achieving Complete and Persistent Tumor Regression.

Embryonic ectoderm development (EED) is a promising therapeutic target for human cancers and other diseases. We report herein the discovery of exceptionally potent and efficacious EED inhibitors. By conformational restriction of a previously reported EED inhibitor, we obtained a potent lead compound. Further optimization of the lead yielded exceptionally potent EED inhibitors. The best compound EEDi-5273 binds to EED with an IC50 value of 0.2 nM and inhibits the KARPAS422 cell growth with an IC50 value of 1.2 nM. It demonstrates an excellent PK and ADME profile, and its oral administration leads to complete and persistent tumor regression in the KARPAS422 xenograft model with no signs of toxicity. Co-crystal structures of two potent EED inhibitors with EED provide a solid structural basis for their high-affinity binding. EEDi-5273 is a promising EED inhibitor for further advanced preclinical development for the treatment of human cancer and other human diseases.

A Pan-Cancer Analysis of SLC12A5 Reveals Its Correlations with Tumor Immunity.

Background Solute carrier family 12 member 5 (SLC12A5) has been reported to play an oncogenic role in certain malignancies. Its prognostic roles and immune mechanisms of action in human cancers, however, remain largely unknown. Methods Data derived from TCGA, GEPIA, and TIMER databases were utilized to delve into the expressing patterns, prognostic values, clinical significances, and tumor immunity of SLC12A5 in tumors. Additionally, the association of SLC12A5 expressions with tumor mutation burden (TMB), methyltransferases, and mismatch repairs (MMRs) was also analyzed. Results Herein, we observed that SLC12A5 was significantly overexpressed in various malignancies, and SLC12A5 levels correlated with overall survival, disease-specific survival, and tumor stage of certain cancers. Furthermore, we noticed that SLC12A5 was distinctly associated with methyltransferases, mismatch repair proteins, TMB, and MSI in human cancers. Conclusions SLC12A5 may act as a potential prognostic and immunological biomarker and therapeutic target for human cancers.

LncRNA HOTAIR: A Potential Prognostic Factor and Therapeutic Target in Human Cancers.

Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of gene expression and physiological processes. LncRNAs are a class of ncRNAs of 200 nucleotides in length. HOX transcript antisense RNA (HOTAIR), a trans-acting lncRNA with regulatory function on transcription, can repress gene expression by recruiting chromatin modifiers. HOTAIR is an oncogenic lncRNA, and numerous studies have determined that HOTAIR is highly upregulated in a wide variety of human cancers. In this review, we briefly summarize the impact of lncRNA HOTAIR expression and functions on different human solid tumors, and emphasize the potential of HOTAIR on tumor prognosis and therapy. Here, we review the recent studies that highlight the prognostic potential of HOTAIR in drug resistance and survival, and the progress of therapies developed to target HOTAIR to date. Furthermore, targeting HOTAIR results in the suppression of HOTAIR expression or function. Thus, HOTAIR knockdown exhibits great therapeutic potential in various cancers, indicating that targeting lncRNA HOTAIR may serve as a promising strategy for cancer therapy. We also propose that preclinical studies involving HOTAIR are required to provide a better understanding of the exact molecular mechanisms underlying the dysregulation of its expression and function in different human cancers and to explore effective methods of targeting HOTAIR and engineering efficient and targeted drug delivery methods in vivo.

Dual Roles of the Activin Signaling Pathway in Pancreatic Cancer.

Activin, a member of the TGF-β superfamily, is involved in many physiological processes, such as embryonic development and follicle development, as well as in multiple human diseases including cancer. Genetic mutations in the activin signaling pathway have been reported in many cancer types, indicating that activin signaling plays a critical role in tumorigenesis. Recent evidence reveals that activin signaling may function as a tumor-suppressor in tumor initiation, and a promoter in the later progression and metastasis of tumors. This article reviews many aspects of activin, including the signaling cascade of activin, activin-related proteins, and its role in tumorigenesis, particularly in pancreatic cancer development. The mechanisms regulating its dual roles in tumorigenesis remain to be elucidated. Further understanding of the activin signaling pathway may identify potential therapeutic targets for human cancers and other diseases.

YB1 regulates miR-205/200b-ZEB1 axis by inhibiting microRNA maturation in hepatocellular carcinoma.

BackgroundY‐box binding protein 1 (YB1 or YBX1) plays a critical role in tumorigenesis and cancer progression. However, whether YB1 affects malignant transformation by modulating non‐coding RNAs remains largely unknown. This study aimed to investigate the relationship between YB1 and microRNAs and reveal the underlying mechanism by which YB1 impacts on tumor malignancy via miRNAs‐mediated regulatory network.MethodsThe biological functions of YB1 in hepatocellular carcinoma (HCC) cells were investigated by cell proliferation, wound healing, and transwell invasion assays. The miRNAs dysregulated by YB1 were screened by microarray analysis in HCC cell lines. The regulation of YB1 on miR‐205 and miR‐200b was determined by quantitative real‐time PCR, dual‐luciferase reporter assay, RNA immunoprecipitation, and pull‐down assay. The relationships of YB1, DGCR8, Dicer, TUT4, and TUT1 were identified by pull‐down and coimmunoprecipitation experiments. The cellular co‐localization of YB1, DGCR8, and Dicer were detected by immunofluorescent staining. The in vivo effect of YB1 on tumor metastasis was determined by injecting MHCC97H cells transduced with YB1 shRNA or shControl via the tail vein in nude BALB/c mice. The expression levels of epithelial to mesenchymal transition markers were detected by immunoblotting and immunohistochemistry assays.ResultsYB1 promoted HCC cell migration and tumor metastasis by regulating miR‐205/200b‒ZEB1 axis partially in a Snail‐independent manner. YB1 suppressed miR‐205 and miR‐200b maturation by interacting with the microprocessors DGCR8 and Dicer as well as TUT4 and TUT1 via the conserved cold shock domain. Subsequently, the downregulation of miR‐205 and miR‐200b enhanced ZEB1 expression, thus leading to increased cell migration and invasion. Furthermore, statistical analyses on gene expression data from HCC and normal liver tissues showed that YB1 expression was positively associated with ZEB1 expression and remarkably correlated with clinical prognosis.ConclusionThis study reveals a previously undescribed mechanism by which YB1 promotes cancer progression by regulating the miR‐205/200b‒ZEB1 axis in HCC cells. Furthermore, these results highlight that YB1 may play biological functions via miRNAs‐mediated gene regulation, and it can serve as a potential therapeutic target in human cancers.

The Significance of Insulin Resistance in Nondiabetic Breast Cancer Patients

Background: The relationship between insulin resistance (IR) and prognostic factors in breast cancer (BC) in premenopausal (pre-M) and postmenopausal (post-M) women is still controversial. We evaluated the potential association between hemoglobin A1c (HbA1c), fasting blood glucose (FBG), fasting insulin levels (FILs), the homeostasis model assessment index (HOMA), and the prognostic factors of BC in nondiabetic patients with pre-M and post-M breast tumors. Methods: We compared 80 nondiabetic patients with pre-M and post-M breast tumors to 60 women with normal mammography as a control. Results: Age, body mass index (BMI), FBG, and HbA1c did not differ between the groups. FIL (P < 0.001) and HOMA-IR (P < 0.001) of the BC group were significantly higher than in the control group. FIL (P < 0.001) and HOMA-IR (P < 0.001) of the BC group were significantly higher than in the control group, for both pre- and post-M patients. FIL and HOMA-IR values were found to be significantly higher in the patients with stage IV BC than in other stages of BC. FIL and HOMA-IR are highly specific and sensitive parameters in their ability to diagnose BC. Conclusions: FIL and HOMA-IR are associated with BC risk in nondiabetic patients with pre-M and post-M breast tumors. When BC risk was evaluated according to the stage of menopause, no difference was observed; only the disease stage was significant. FIL and IR may function as potential biomarkers and therapeutic targets for human cancers. J Endocrinol Metab. 2021;11(2):42-48 doi: https://doi.org/10.14740/jem729

ADAMTS9-AS2: A Functional Long Non-coding RNA in Tumorigenesis.

Long non-coding RNAs (lncRNA) have been identified as novel molecular regulators in cancers. LncRNA ADAMTS9-AS2 can mediate the occurrence and development of cancer through various ways, such as regulating miRNAs, activating the classical signaling pathways in cancer, and so on, which have been studied by many scholars. In this review, we summarize the molecular mechanisms of ADAMTS9-AS2 in different human cancers. Through a systematic search of PubMed, lncRNA ADAMTS9-AS2 mediated molecular mechanisms in cancer are summarized inductively. ADAMTS9-AS2 aberrantly expression in different cancers is closely related to cancer proliferation, invasion, migration, and inhibition of apoptosis. The involvement of ADAMTS9-AS2 in DNA methylation, mediating PI3K / Akt / mTOR signaling pathways, and regulating miRNAs and proteins, shows its significant potential as a therapeutic cancer target. LncRNA ADAMTS9-AS2 can become a promising biomolecular marker and a therapeutic target for human cancer.

Therapeutic targeting of FOS in mutant TERT cancers through removing TERT suppression of apoptosis via regulating survivin and TRAIL-R2

The telomerase reverse transcriptase (TERT) has long been pursued as a direct therapeutic target in human cancer, which is currently hindered by the lack of effective specific inhibitors of TERT. The FOS/GABPB/(mutant) TERT cascade plays a critical role in the regulation of mutant TERT, in which FOS acts as a transcriptional factor for GABPB to up-regulate the expression of GABPB, which in turn activates mutant but not wild-type TERT promoter, driving TERT-promoted oncogenesis. In the present study, we demonstrated that inhibiting this cascade by targeting FOS using FOS inhibitor T-5224 suppressed mutant TERT cancer cells and tumors by inducing robust cell apoptosis; these did not occur in wild-type TERT cells and tumors. Mechanistically, among 35 apoptotic cascade-related proteins tested, the apoptosis induced in this process specifically involved the transcriptional activation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) and inactivation of survivin, two key players in the apoptotic cascade, which normally initiate and suppress the apoptotic cascade, respectively. These findings with suppression of FOS were reproduced by direct knockdown of TERT and prevented by prior knockdown of TRAIL-R2. Further experiments demonstrated that TERT acted as a direct transcriptional factor of survivin, up-regulating its expression. Thus, this study identifies a therapeutic strategy for TERT promoter mutation-driven cancers by targeting FOS in the FOS/GABPB/(mutant) TERT cascade, circumventing the current challenge in pharmacologically directly targeting TERT itself. This study also uncovers a mechanism through which TERT controls cell apoptosis by transcriptionally regulating two key players in the apoptotic cascade.

The MEK/ERK Network as a Therapeutic Target in Human Cancer.

The RAS-RAF-MEK-ERK pathway is the most well-studied of the MAPK cascades and is critical for cell proliferation, differentiation, and survival. Abnormalities in regulation resulting from mutations in components of this pathway, particularly in upstream proteins, RAS and RAF, are responsible for a significant fraction of human cancers and nearly all cutaneous melanomas. Activation of receptor tyrosine kinases by growth factors and various extracellular signals leads to the sequential activation of RAS, RAF, MEK, and finally ERK, which activates numerous transcription factors and facilitates oncogenesis in the case of aberrant pathway activation. While extensive studies have worked to elucidate the activation mechanisms and structural components of upstream MAPK components, comparatively less attention has been directed toward the kinases, MEK and ERK, due to the infrequency of oncogenic-activating mutations in these kinases. However, acquired drug resistance has become a major issue in the treatment of RAS- and RAF-mutated cancers. Targeting the terminal kinases in the MAPK cascade has shown promise for overcoming many of these resistance mechanisms and improving treatment options for patients with MAPK-aberrant cancers. Here, we will describe the role of MEK and ERK in MAPK signaling and summarize the current understanding of their interaction and activation mechanisms. We will also discuss existing approaches for targeting MEK and ERK, and the benefits of alternative strategies. Areas requiring further exploration will be highlighted to guide future research endeavors and aid in the development of alternative therapeutic strategies to combat surmounting drug resistance in treating MAPK-mediated cancers. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/3/361/F1.large.jpg.