Category Archives: Mechanism

MEK1/2 inhibition delays progression of uveal melanoma

A multicentre, phase 2 trial has shown that selumetinib (an inhibitor of MEK1 and MEK2) provided significantly better progression-free survival and tumour response than did chemotherapy in patients with advanced uveal melanoma.

“Mutations in G-proteins GNAQ and GNA11 are present in 90–95% of patients with metastatic uveal melanoma”, explained senior author Gary Schwartz (Columbia University School of Medicine, Herbert Irving Comprehensive Cancer Center, New York, NY, USA). “These mutations activate a majority of signalling pathways, including MAPK, AKT, and PKC. In laboratory studies, selumetinib completely blocked the MEK pathway, and inhibited growth of uveal melanoma cells in culture.”

To study the efficacy of inhibiting MEK1/2 in uveal melanoma, 101 patients were randomly assigned to receive oral selumetinib or standard chemotherapy. Progression-free survival was significantly longer with selumetinib (15·9 weeks [95% CI 8·4–21·1]) than with chemotherapy (7 weeks [4·3–8·4]; hazard ratio [HR] 0·46 [0·30–0·71], p<0·001); no significant difference in overall survival was seen (11·8 months [95% CI 9·8–15·7] vs 9·1 months [6·1–11·1], respectively; HR 0·66 [0·41–1·06], p=0·09). 49% of patients assigned to selumetinib had tumour regression, whereas no objective responses were reported in the chemotherapy group. 65 (97%) of 67 patients receiving selumetinib had treatment-related adverse events, and 25 (37%) needed dose reductions.


“Targeted therapy is a promising way forward in uveal melanoma”, commented Patrick Ott (Dana-Farber Cancer Institute, Boston, MA, USA). “No systemic treatment was previously shown to work in this disease.”

Lead author Richard Carvajal (Memorial Sloan Kettering Cancer Center, New York, NY, USA) said that future studies include SUMIT (NCT01974752), a phase 3 trial of selumetinib in combination with dacarbazine versus chemotherapy alone, and (based on preclinical data showing that efficacy of MEK inhibition can be enhanced with the addition of AKT or PKC inhibition) a study of trametinib alone or in combination with GSK2141795 and a study of MEK162 and AEB071.

Sapna Patel (MD Anderson Cancer Center, Houston, TX, USA) said, “For the first time in uveal melanoma, we can use targeted therapy to effect tumour response. Targeted therapy with a MEK inhibitor really can potentially be the backbone of new therapy for this tumour.”


Is YAP the Key to Targeted Therapy?

Malignant melanomas that arise from the iris, ciliary body, and choroid layers of the eye-collectively referred to as uveal melanomas—represent the most common primary cancer of the eye and the second most common form of melanoma. Until recently, the identification of effective therapies for metastatic uveal melanoma has been hampered by a lack of known driver mutations. This situation has changed in recent years with the discovery of several common driver mutations, which has opened the door to rational targeted therapies.

Mutually exclusive mutations in the G protein-coupled receptor (GPCR) alpha subunits GNAQ and GNA11 (encoding Gq and G11 proteins, respectively) are present in ∼85% of uveal melanocytic tumors, including benign nevi, primary melanomas of all stages, and metastatic lesions. This spectrum suggests that GNAQ/11 mutations occur early and may even represent initiating events in tumorigenesis. These mutations occur as single amino acid substitutions at residues Q209 or R183, and they abrogate the intrinsic GTPase activity that normally serves to inactivate the subunit. As such, these inactivating mutations result in constitutive activation of oncogenic Gq/11 subunits. The recessive nature of these mutations at the molecular level, despite their dominant action at the cellular level, has posed a major challenge for direct pharmacologic inhibition. Instead, most efforts have focused on inhibiting downstream targets of activated Gq/11. The best understood target of Gq/11 is phospholipase C beta (PLCβ), which cleaves phosphatidylinositol (4,5)-bisphosphate (PIP2) to yield diacylglycerol (DAG) and inositol triphosphate (IP3). Both products promote stimulation of protein kinase C (PKC), which leads to activation of the mitogen-activated protein kinase (MAPK or MEK) pathway and cell proliferation. MEK and PKC inhibitors inhibit the proliferation of Gq/11 mutant uveal melanoma cell lines in vitro. Yet, clinical trials so far have shown little or no activity of such agents in patients with metastatic uveal melanoma, raising the question of whether there may be other targets that are critical for therapeutic inhibition in cancers harboring oncogenic forms of Gq/11.


One such target may be the Hippo tumor suppressor pathway, which controls tissue growth and cell fate through the regulation of cell proliferation and apoptosis . Key effectors of the pathway include the homologous oncoproteins YAP and TAZ, which promote tissue growth by regulating the activity of transcription factors such as TEADs and SMADs. In most proliferating cells, YAP is localized in the nucleus in its active form. Hippo pathway signaling leads to phosphorylation of YAP by the serine/threonine-protein kinases LATS1/2, resulting in YAP inactivation and retention in the cytoplasm and degradation via the proteasome.


Feng et al. and Yu et al. publicized studies showing that Gq/11 mutants found in uveal melanoma promote tumorigenesis by activating YAP. Mutant Gq/11, but not wild-type Gq/11, was found to trigger dephosphorylation and nuclear localization of YAP, associated with YAP-dependent transcription. Importantly, this activity of mutant Gq/11 is independent of PLCβ. In uveal melanoma cell lines and human tumor samples, there was a strong correlation between the presence of Gq/11 mutations and activated YAP, as indicated by its nuclear localization and increased levels of unphosphorylated YAP.

The question then arises as to whether this YAP activation by mutant Gq/11 is mediated solely through inhibition of LATS1/2. In their current article and in a recent publication by the same group show that activation of YAP by mutant Gq requires the guanine nucleotide exchange factor, Trio, and downstream small GTPases RhoA and Rac1. Activation of RhoA and Rac1 induces actin polymerization of G-actin to F-actin, triggering dissociation of the cytoskeletal-associated protein angiomotin (AMOT) from YAP, thereby allowing YAP to translocate from the cytoplasm to the nucleus to activate YAP-dependent transcription. Thus, mutant Gq/11 may activate YAP not only by inhibiting LATS1/2, but also by promoting actin polymerization independently of the canonical Hippo pathway.

Although these findings are promising, it is unlikely that inhibition of mutant Gq/11 signaling alone will be sufficient for treating metastatic uveal melanoma. Mutant Gq and G11 are relatively weak oncoproteins that are only able to transform immortalized melanocytes that have been genetically altered to be deficient in the p53 and p16/CDK4/RB pathways. Nevertheless, these findings will play an important role in the ongoing quest for effective therapy against metastatic uveal melanoma.

AEG-1/MTDH/LYRIC may be a viable target as an anticancer agent for a wide variety of cancers

AEG-1/MTDH/LYRIC has been shown to promote cancer progression and development. Overexpression of AEG-1/MTDH/LYRIC correlates with angiogenesis, metastasis, and chemoresistance to various chemotherapy agents in cancer cells originating from a variety of tissues. Xiangbing Meng focused on the role of AEG-1/MTDH/LYRIC in drug resistance. Their mechanistic studies have shown that AEG-1/MTDH/LYRIC is involved in classical oncogenic pathways including Ha-Ras, myc, NFκB, and PI3K/Akt. AEG-1/MTDH/LYRIC also promotes protective autophagy by activating AMP kinase and autophagy-related gene 5.



Another reported mechanism by which AEG-1/MTDH/LYRIC regulates drug resistance is by increasing loading of multidrug resistance gene (MDR) 1 mRNA to the polysome, thereby facilitating MDR1 protein translation. More recently, a novel function for AEG-1/MTDH/LYRIC as an RNA-binding protein was elucidated, which has the potential to impact expression of drug sensitivity or resistance genes. Finally, AEG-1/MTDH/LYRIC acts in microRNA-directed gene silencing via an interaction with staphylococcal nuclease and tudor domain containing 1, a component of the RNA-induced silencing complex. Altered microRNA expression and activity induced by AEG-1/MTDH/LYRIC represent an additional way that AEG-1/MTDH/LYRIC may cause drug resistance in cancer. The multiple functions of AEG-1/MTDH/LYRIC in drug resistance highlight that it is a viable target as an anticancer agent for a wide variety of cancers.

To Shift Gears of Prostate Cancer Migration

Alteration of lipid metabolism is increasingly recognized as a signature of cancer cells. It’s  reported that accumulation of aberrant cholesteryl ester is found in advanced prostate cancers with PTEN loss and PI3K/AKT activation. And inhibition of cholesterol esterification impairs cancer aggressiveness.


Prostate cancer cells becoming rounder and sprouting projections

Additionally , the scientists from The University of Manchester combine prostate cancer cells in the lab with arachidonic acid (AA), an omega-6 fatty acid that has been shown to attract prostate cancer cells to the bone marrow, and uncover a link between cholesterol and prostate cancer’s ability to spread to the bones in a study published in the British Journal of Cancer.

They ascertain how naturally occurring fatty acids in the bone marrow directly interact with the body’s system of manufacturing cholesterol to enhance prostate cancer cells’ ability to spread. These findings give clues to prostate cancer migration and help explain why taking statins – commonly used cholesterol-lowering drugs – is thought to slow the progress of the disease in some cases.

“Prostate cancer spreading to the bones is a major challenge for doctors and unfortunately it’s very difficult to treat. ” said Nell Barrie, senior science information manager at Cancer Research , “Altering cholesterol metabolism or blocking the ways in which prostate cancer cells are able to change their shape, and thereby their ability to spread, could lead to major advances in treating men with aggressive forms of the disease.”


Arachidonic acid induction of Rho mediated transendothelial migration in prostate cancer British Journal of Cancer. Br J Cancer. 2014 Apr 15;110(8):2099-108.

Cholesteryl Ester Accumulation Induced by PTEN Loss and PI3K/AKT Activation Underlies Human Prostate Cancer Aggressiveness. Cell Metabolism, 2014, 3(19):393-406