MEK1/2 Inhibitors: Molecular Activity and Resistance Mechanisms

Abstract

Aberrant activation of the three-layered protein kinase cascade, Raf/MEK/ERK, is often detected in human cancer, which is mainly attributed to the oncogenic alterations of RAF, or its upstream activators RAS or cell surface receptor tyrosine kinases. Deregulated activity of the Raf/MEK/ERK pathway drives uncontrolled tumor cell proliferation and survival, thus providing a rational therapeutic target for the treatment of many cancers. While Raf, MEK1/2, and ERK1/2 are equally important targets for the design of therapeutic small molecular weight inhibitors, the effort to develop MEK1/2-specific inhibitors has been greatly successful. Particularly, MEK1/2 have been relatively advantageous for the design of highly selective ATP-noncompetitive inhibitors. Indeed, a plethora of highly selective and potent MEK1/2 inhibitors are now available and many of those inhibitors have been evaluated for their therapeutic potential. Herein, we review different MEK1/2 inhibitors that have been studied for their inhibitory mechanisms and therapeutic potential in cancer. Some of the key structural features of MEK1/2 that are important for the efficacy of these inhibitors are also discussed. In addition, we discuss current challenges and future prospective in using these advanced MEK1/2 inhibitors for cancer therapy.

RETRACTED ARTICLE: Decreased expression of miR-939 contributes to chemoresistance and metastasis of gastric cancer via dysregulation of SLC34A2 and Raf/MEK/ERK pathway

“…Numerous reports have shown the aberrant activation of Raf/MEK/ERK pathway in variety of human cancers [36, 37]. Recent studies also demonstrated aberrant regulation of this pathway was associated with cancer chemoresistance [14, 15]. In the present study, we observed that miR-939 overerxpression in GC cells significantly decreased MEK1/2 phosphorylation and Raf-1 level, while restoration of SLC34A2 rescued these effects.…”

Modulation of Ras/ERK and Phosphoinositide Signaling by Long-Chain n-3 PUFA in Breast Cancer and Their Potential Complementary Role in Combination with Targeted Drugs

“…While, on one hand, this observation indicates that just one of them can be enough to dysregulate the entire Ras/Raf/MEK/ERK1/2 cascade, on the other hand it further supports the critical role played by the abnormal activation of this cascade in carcinogenesis. As analyzed in detail in a recent review by Wu and Park [22], RAS mutations are detected in more than half of the pancreas cancers, and in about a third of colon, biliary tract, and skin cancers, as well as in around a fifth of small intestine or lung cancers. A series of other cancers (ovary, salivary glands, urinary tract, cervix, endometrium, upper aero-digestive tract, prostate, thyroid, and hemopoietic/lymphoid cells) [22] are characterized by RAS mutations, although with slightly lower proportions (ranging from 14% to 18%).…”

“…As analyzed in detail in a recent review by Wu and Park [22], RAS mutations are detected in more than half of the pancreas cancers, and in about a third of colon, biliary tract, and skin cancers, as well as in around a fifth of small intestine or lung cancers. A series of other cancers (ovary, salivary glands, urinary tract, cervix, endometrium, upper aero-digestive tract, prostate, thyroid, and hemopoietic/lymphoid cells) [22] are characterized by RAS mutations, although with slightly lower proportions (ranging from 14% to 18%). Also, mutations in BRAF, particularly those involving the Valine600 codon, are found at very high percentages in several cancers.…”

“…Also, mutations in BRAF, particularly those involving the Valine600 codon, are found at very high percentages in several cancers. Whereas, for instance, 100% of hairy cell leukemia is characterized by this mutation, it has been detected in 50%–70% of melanomas, 57% of Langerhans cell histiocytosis, 40% of papillary thyroid cancers, and more than 30% of low-grade ovarian carcinomas [22]. Given the wide diffusion and the role played by these mutations in a large number of malignancies, great efforts are being made in the development of drugs specifically targeting members of the RAS/RAF/MEK/ERK1/2 cascade.…”

Sanguinarine inhibits growth and invasion of gastric cancer cells via regulation of the DUSP4/ERK pathway

“…Aberrant activation of the Raf/MEK/ERK, which drives uncontrolled tumour cell proliferation and survival, is detected in a variety of human cancers [47][48][49][50]. Cell surface receptor tyrosine kinases, or oncogenic alterations of RAF, or its upstream activators RAS, contribute to aberrant activation of this pathway [51][52][53][54]. DUSP4, a dual-specificity phosphatase, can inactivate Raf/MEK/ERK signalling pathway through dephosphorylating p-ERK.…”