Thrombospondin-1 Mediates Oncogenic Ras–Induced Senescence in Premalignant Lung Tumors

Progression of premalignant lesions is restrained by oncogene-induced senescence. Oncogenic Ras triggers senescence in many organs, including the lung, which exhibits high levels of the angiogenesis inhibitor thrombospondin-1 (TSP-1). The contribution of TSP-1 upregulation to the modulation of tumorigenesis in the lung is unclear. Using a mouse model of lung cancer, we have shown that TSP-1 plays a critical and cell-autonomous role in suppressing Kras-induced lung tumorigenesis independent of its antiangiogenic function. We found that oncogenic Kras–induced TSP-1 upregulation in a p53-dependent manner. TSP-1 functioned in a positive feedback loop to stabilize p53 by interacting directly with activated ERK. TSP-1 tethering of ERK in the cytoplasm promoted a level of MAPK signaling that was sufficient to sustain p53 expression and a senescence response.


Mechanism of MEK Inhibition Determines Efficacy in Mutant KRAS- Versus BRAF-Driven Cancers

“KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease1. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours23, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF.”


Mechanism of MEK Inhibition Determines Efficacy in Mutant KRAS- Versus BRAF-Driven Cancers

“KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease1. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours23, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF.”


Mechanism of MEK Inhibition Determines Efficacy in Mutant KRAS- Versus BRAF-Driven Cancers

“KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease1. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours23, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF.”


Identification of Transcriptional Subgroups in EGFR-Mutated and EGFR/KRAS-Wild Type Lung Adenocarcinoma Reveals Gene Signatures Associated with Patient Outcome

We sought to determine whether transcriptional subgroups of clinical relevance exist within EGFR-mutated, KRAS-mutated, or EGFR and KRAS-wild type (EGFRwt/KRASwt) adenocarcinomas. We identified transcriptional subgroups in EGFR-mutated and EGFRwt/KRASwt adenocarcinomas with significant differences in clinicopathological characteristics and patient outcome, not limited to a mutation specific setting.


Indirect Approach May Finally Make Inhibition of Cancer Gene KRAS Possible

The KRAS gene is mutated in one-third of tumors and its importance in promoting the growth of cancer cells has been known for decades. However, efforts to develop a KRAS inhibitor have so far been unsuccessful. Now, researchers may have found a way to suppress KRAS indirectly using a drug called deltarasin. To function properly, KRAS needs to be attached to the cell’s membrane, a process aided by the transport protein PDE-δ. Deltarasin blocks PDE-δ, preventing KRAS from anchoring to the cell membrane. A recent study showed that deltarasin reduced the growth of KRAS-mutant tumor cells both in cell culture and in a mouse model of pancreatic cancer.


Hexokinase 2 Is Required for Tumor Initiation and Maintenance and Its Systemic Deletion Is Therapeutic in Mouse Models of Cancer

“Accelerated glucose metabolism is a common feature of cancer cells. Hexokinases catalyze the first committed step of glucose metabolism. Hexokinase 2 (HK2) is expressed at high level in cancer cells, but only in a limited number of normal adult tissues. Using Hk2conditional knockout mice, we showed that HK2 is required for tumor initiation and maintenance in mouse models of KRas-driven lung cancer, and ErbB2-driven breast cancer, despite continued HK1 expression. Similarly, HK2 ablation inhibits the neoplastic phenotype of human lung and breast cancer cells in vitro and in vivo. Systemic Hk2 deletion is therapeutic in mice bearing lung tumors without adverse physiological consequences. Hk2 deletion in lung cancer cells suppressed glucose-derived ribonucleotides and impaired glutamine-derived carbon utilization in anaplerosis.”


Genetic Characteristics of Women With Lung Cancer Differ Depending on Smoking History

Few studies so far have focused specifically on lung cancer in women, despite increasing evidence of differences in lung cancer features between women and men. A striking example is the higher rate among women of nonsmokers who develop lung cancer. A recent study of women with lung adenocarcinoma, a type of non-squamous non-small cell lung cancer (NSCLC), found that those who had never smoked were much more likely to have mutations in the EGFR gene and/or abnormally high levels of estrogen receptors, while smokers were more likely to have mutations in the KRAS gene. Based on these findings, a new phase II clinical trial will explore the effectiveness of treating postmenopausal, nonsmoking women who have advanced non-squamous lung cancer with EGFR inhibitors and anti-estrogen drugs.


National Cancer Institute's 'RAS Project' Takes Aim at Common Cancer-Driving Protein

The National Cancer Institute (NCI) is organizing a massive collaborative initiative between its laboratory and hundreds of outside researchers to discover cancer treatments targeting a class of genes called RAS genes and their products, RAS proteins. RAS genes, including their most common form, KRAS, are mutated in one-third of all cancers. Although the important role of RAS in cancer has been known for over 30 years, no treatments targeting RAS have been developed so far, because RAS proteins lack a ‘binding site’ where drugs could attack. However, recent research has uncovered potential weaknesses in RAS that future treatment might exploit. The NCI’s RAS Project aims to ‘crowdsource’ the expertise of many researchers to better understand and tackle RAS.