Small Molecule Inhibition of the KRAS–PDEδ Interaction Impairs Oncogenic KRAS Signalling

“The KRAS oncogene product is considered a major target in anticancer drug discovery123. However, direct interference with KRAS signalling has not yet led to clinically useful drugs34567,8. Correct localization and signalling by farnesylated KRAS is regulated by the prenyl-binding protein PDEδ, which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm91011. Here we report that interfering with binding of mammalian PDEδ to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes.”


Clinical Trial Reveals Patients' Willingness to Undergo Genetic Testing for Personalized Cancer Treatment

A recently completed clinical trial examining the use of genetic testing to direct cancer treatment was able to exceed its enrollment goal of 600 participants in less than 2 years instead of the expected 5 years. Patients were willing to participate even though they had to undergo an additional biopsy, revealing considerable interest in personalized treatment based on genetic tests. The trial confirmed that erlotinib (Tarceva) is highly effective in non-small cell lung cancer (NSCLC) patients with a mutation in the EGFR gene. It also found that NSCLC patients with mutations in the KRAS gene did not benefit from the novel cancer drug selumetinib. In contrast, not enough small cell lung cancer (SCLC) patients had any of the investigated mutations to properly test how they responded to treatments. Such mutations will require trials involving thousands of patients to draw reliable conclusions.


Clinical Trial Reveals Patients' Willingness to Undergo Genetic Testing for Personalized Cancer Treatment

A recently completed clinical trial examining the use of genetic testing to direct cancer treatment was able to exceed its enrollment goal of 600 participants in less than 2 years instead of the expected 5 years. Patients were willing to participate even though they had to undergo an additional biopsy, revealing considerable interest in personalized treatment based on genetic tests. The trial confirmed that erlotinib (Tarceva) is highly effective in non-small cell lung cancer (NSCLC) patients with a mutation in the EGFR gene. It also found that NSCLC patients with mutations in the KRAS gene did not benefit from the novel cancer drug selumetinib. In contrast, not enough small cell lung cancer (SCLC) patients had any of the investigated mutations to properly test how they responded to treatments. Such mutations will require trials involving thousands of patients to draw reliable conclusions.


Clinical Trial Reveals Patients' Willingness to Undergo Genetic Testing for Personalized Cancer Treatment

A recently completed clinical trial examining the use of genetic testing to direct cancer treatment was able to exceed its enrollment goal of 600 participants in less than 2 years instead of the expected 5 years. Patients were willing to participate even though they had to undergo an additional biopsy, revealing considerable interest in personalized treatment based on genetic tests. The trial confirmed that erlotinib (Tarceva) is highly effective in non-small cell lung cancer (NSCLC) patients with a mutation in the EGFR gene. It also found that NSCLC patients with mutations in the KRAS gene did not benefit from the novel cancer drug selumetinib. In contrast, not enough small cell lung cancer (SCLC) patients had any of the investigated mutations to properly test how they responded to treatments. Such mutations will require trials involving thousands of patients to draw reliable conclusions.


Pooled Analysis of the Prognostic and Predictive Effects of KRAS Mutation Status and KRAS Mutation Subtype in Early-Stage Resected Non–Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy

We undertook this analysis of KRAS mutation in four trials of adjuvant chemotherapy (ACT) versus observation (OBS) to clarify the prognostic/predictive roles of KRAS in non–small-cell lung cancer (NSCLC).

KRAS mutation status is not significantly prognostic. The potential interaction in patients with codon-13 mutations requires validation. At this time, KRAS status cannot be recommended to select patients with NSCLC for ACT.


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…”


New Drug Overcomes Resistance to BRAF Inhibitors in Mice and Cultured Human Cells

An experimental drug may strengthen treatments that target melanomas with mutations in the BRAF gene, reported researchers from the pharmaceutical company Merck at the American Association for Cancer Research’s 2013 meeting. Treatments that target BRAF often stop working because tumors activate a related protein called ERK, which is the target of Merck’s new drug. Called SCH772984, the drug inhibits ERK in cultured human tumor cells with BRAF, NRAS, or KRAS mutations; slows cell division in human tumor cells that resist treatments that target BRAF or MEK; and shrinks tumors in mice. The researchers have begun a phase I clinical trial of an ERK inhibitor in people with tumors.


RHOA-FAK Is a Required Signaling Axis for the Maintenance of KRAS-Driven Lung Adenocarcinomas

Non–small cell lung cancer (NSCLC) often expresses mutant KRAS together with tumor-associated mutations of the CDKN2A locus, which are associated with aggressive, therapy-resistant tumors. Suppression of RHOA or FAK induces cell death selectively in mutant KRAS;INK4A/ARF-deficient lung cancer cells. Furthermore, pharmacologic inhibition of FAK caused tumor regression specifically in the high-grade lung cancer that developed in mutant Kras;Cdkn2a-null mice.


New Lung Cancer Drug Ganetespib Shows Mixed Results in Clinical Trial

Results from an ongoing phase II clinical trial suggest that the new drug ganetespib may be effective in a subset of patients with advanced non-small cell lung cancer (NSCLC). People with mutations in the genes EGFR or KRAS, who had been the original focus of the study, did not benefit significantly from the drug. However, among patients with mutations in the ALK gene who had not been treated previously with crizotinib (Xalkori), half seemed to benefit from ganetespib. This finding is based on a small number of patients, but Synta Pharmaceuticals, the company developing ganetespib, will investigate it further in a clinical trial focusing specifically on ALK-mutant NSCLC.