The Trouble With KRAS

Mutations in the gene that encodes the KRAS protein are frequently encountered in various human cancers. They are found in about 30% of non-small cell lung cancers (NSCLCs), making KRAS the single most common gene mutated in this cancer. The rate of KRAS mutations in other cancers, such as pancreatic or colorectal, is even higher.

A mutant KRAS protein that is always in the “on” position activates many signaling pathways, many of which lead to unrestrained growth and proliferation of cancer cells. This makes KRAS an appealing treatment target. However, challenges abound, and researchers are exploring several different approaches to treating KRAS-mutant cancers.

Unlike mutations in proteins known as receptor tyrosine kinases, like EGFR or ALK, mutated KRAS is a very difficult protein to target with cancer drugs. (So much so that the National Institutes of Health (NIH) has undertaken a special effort to intensify the effort towards successful targeting of mutant KRAS, known as the RAS Initiative.) Continue reading…

Melanoma: A 2013 ‘Progress Report’

The past year saw some remarkable advances in melanoma clinical research and treatment. This feature explores the most notable melanoma news of 2013: Continue reading…

Another Option in Our KIT of Effective Therapies for Advanced Melanoma

“Hodi et al reported the final results of a multicenter phase II trial of imatinib in patients with advanced melanoma harboring mutations or amplification of the KIT proto-oncogene. KIT is a transmembrane receptor tyrosine kinase, normally expressed on melanocytes, that plays a critical role in melanocyte migration, survival, proliferation, and differentiation. Mutations and amplification of KIT have been identified in melanomas arising from mucosal, acral or chronically sun-damaged surfaces, and they characterize a distinct genetic subset of disease. The alterations identified are, in most instances, mutually exclusive of BRAF and NRAS mutations and lead to constitutive activation of downstream signaling pathways including the MAPK, PI3K/AKT, and JAK/STAT pathways.”

Phase II Study of Selumetinib (sel) Versus Temozolomide (TMZ) in Gnaq/Gna11 (Gq/11) Mutant (mut) Uveal Melanoma (UM)

“Gq/11 mutations are early oncogenic events in UM resulting in MAPK pathway activation. We demonstrated decreased viability in UM cell lines harboring Gq/11 mut with sel, a small molecule inhibitor of MEK1/2 (Ambrosini, CCR 2012).”

RAF Inhibitors Activate the MAPK Pathway by Relieving Inhibitory Autophosphorylation

“ATP competitive inhibitors of the BRAFV600E oncogene paradoxically activate downstream signaling in cells bearing wild-type BRAF (BRAFWT). In this study, we investigate the biochemical mechanism of wild-type RAF (RAFWT) activation by multiple catalytic inhibitors using kinetic analysis of purified BRAFV600E and RAFWT enzymes. We show that activation of RAFWT is ATP dependent and directly linked to RAF kinase activity…”

IQGAP1 Scaffold-Kinase Interaction Blockade Selectively Targets RAS-MAP Kinase–Driven Tumors

“Upregulation of the ERK1 and ERK2 (ERK1/2) MAP kinase (MAPK) cascade occurs in >30% of cancers1, often through mutational activation of receptor tyrosine kinases or other upstream genes, including KRAS and BRAF2. Efforts to target endogenous MAPKs are challenged by the fact that these kinases are required for viability in mammals34. Additionally, the effectiveness of new inhibitors of mutant BRAF has been diminished by acquired tumor resistance through selection for BRAF-independent mechanisms of ERK1/2 induction…”

Preclinical Study Indicates Potential for Novel Inhibitor to Overcome Drug Resistance Induced by RAF, MEK Inhibitors

WASHINGTON, D.C. — A new class of investigational medicines may help to treat patients with cancers driven by mutations in genes such as BRAF or KRAS/NRAS, including those patients who have become resistant to therapies that target BRAF directly,…

Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo

New study suggests the combination of  targeting  the MEK/ERK and PI3K/mTOR pathways has antitumor activity and could be a therapeutic option in the treatment of NRAS mutant melanoma, for which there are currently no effective therapies.