Genomic classification of the RAS network identifies a personalized treatment strategy for lung cancer

El-Chaar, Nader N.; Piccolo, Stephen R.; Boucher, Kenneth M.; Cohen, Adam L.; Chang, Jeffrey T.; Moos, Philip J.; Bild, Andrea

doi:10.1016/j.molonc.2014.05.005

Cited by 12 publications

(17 citation statements)

References 69 publications

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“…MEK162 and PD-0325901 are second-generation MEK1/2 inhibitors currently evaluated in molecularly driven phase I/II trials (clinicaltrials.gov: NCT02022982). Based on a genomic classification, the double inhibition of MEK and EGFR proteins is a promising therapeutic strategy [41]. Early-phase trials are assessing currently such associations: MEK162-erlotinib (clinicaltrials.gov: NCT01859026) or PD-0325901-dacomitinib (clinicaltrials.gov: NCT02039336).…”

Section: If Direct Blocking Of Rasmentioning

confidence: 99%

KRASoncogene in lung cancer: focus on molecularly driven clinical trials

et al. 2016

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KRAS mutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically for KRAS-mutated NSCLC patients. Direct inhibition of RAS activation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients' clinical outcomes. One phase III trial in such a setting is ongoing. Double inhibition of MEK and epidermal growth factor receptor proteins is currently being assessed in early-phase trials. The association with mammalian target of rapamycin pathway inhibition leads to non-manageable toxicity. Other strategies, such as inhibition of molecular heat-shock proteins 90 or focal adhesion kinase are currently assessed. Abemaciclib, a cyclindependent kinase 4/6 inhibitor, showed promising results in a phase I trial, with a 54% disease control rate. Results of an ongoing phase III trial are warranted. Immunotherapy might be the next relevant step in KRAS-mutated NSCLC management due to the high burden of associated mutations and neo-antigens. @ERSpublications MEK inhibition and immunotherapy are very promising therapeutic advances in KRAS-mutated nonsmall cell lung cancer http://ow.ly/U2ohp KRAS mutations in lung cancer: epidemiology and clinical outcomesSince the beginning of the 21st century, the paradigm of precision medicine has shaken up the landscape of lung cancer classification and treatment. The discovery of cancer-related driver molecular abnormalities led to the development of efficient targeted therapies. RAS proteins are GTP kinases, discovered in the 1960s, whose GTP-RAS active isoform stimulates several pathways involved in cellular growth. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations are found in ∼25-35% of newly diagnosed nonsmall cell lung cancer (NSCLC), with a higher proportion in the adenocarcinoma subtype [1,2]. Figure 1 summarises the main amino acid substitutions and genomic features that are associated with KRAS mutations in NSCLC [3,4]. Other molecular abnormalities related to RAS pathway activation are diagnosed in 25% of NSCLC cases, such as epidermal growth factor receptor (EGFR) (10-23%), BRAF mutations (2%), MET amplifications (2%), human epidermal growth factor (HER)2 (1%) and NRAS (0.2%) mutations. Loss of the negative regulator neurofibromin is found in ∼11% of other cases.

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Section: If Direct Blocking Of Rasmentioning

confidence: 99%

KRASoncogene in lung cancer: focus on molecularly driven clinical trials

et al. 2016

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“…Pathway activation has been used to predict drug response to targeted therapies in cell lines [52, 54, 55], but to the best of our knowledge, this is the first study which measures activity of seven GFRN members concurrently at the pathway level in patient samples. In this study, 1119 breast tumors were profiled for GFRN activity across The Cancer Genome Atlas (TCGA) and across 55 breast cancer cell lines from the Integrative Cancer Biology Program (ICBP43) [56, 57] (Fig.…”

Section: Introductionmentioning

confidence: 99%

Activity of distinct growth factor receptor network components in breast tumors uncovers two biologically relevant subtypes

et al. 2017

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BackgroundThe growth factor receptor network (GFRN) plays a significant role in driving key oncogenic processes. However, assessment of global GFRN activity is challenging due to complex crosstalk among GFRN components, or pathways, and the inability to study complex signaling networks in patient tumors. Here, pathway-specific genomic signatures were used to interrogate GFRN activity in breast tumors and the consequent phenotypic impact of GRFN activity patterns.MethodsNovel pathway signatures were generated in human primary mammary epithelial cells by overexpressing key genes from GFRN pathways (HER2, IGF1R, AKT1, EGFR, KRAS (G12V), RAF1, BAD). The pathway analysis toolkit Adaptive Signature Selection and InteGratioN (ASSIGN) was used to estimate pathway activity for GFRN components in 1119 breast tumors from The Cancer Genome Atlas (TCGA) and across 55 breast cancer cell lines from the Integrative Cancer Biology Program (ICBP43). These signatures were investigated for their relationship to pro- and anti-apoptotic protein expression and drug response in breast cancer cell lines.ResultsApplication of these signatures to breast tumor gene expression data identified two novel discrete phenotypes characterized by concordant, aberrant activation of either the HER2, IGF1R, and AKT pathways (“the survival phenotype”) or the EGFR, KRAS (G12V), RAF1, and BAD pathways (“the growth phenotype”). These phenotypes described a significant amount of the variability in the total expression data across breast cancer tumors and characterized distinctive patterns in apoptosis evasion and drug response. The growth phenotype expressed lower levels of BIM and higher levels of MCL-1 proteins. Further, the growth phenotype was more sensitive to common chemotherapies and targeted therapies directed at EGFR and MEK. Alternatively, the survival phenotype was more sensitive to drugs inhibiting HER2, PI3K, AKT, and mTOR, but more resistant to chemotherapies.ConclusionsGene expression profiling revealed a bifurcation pattern in GFRN activity represented by two discrete phenotypes. These phenotypes correlate to unique mechanisms of apoptosis and drug response and have the potential of pinpointing targetable aberration(s) for more effective breast cancer treatments.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0429-x) contains supplementary material, which is available to authorized users.

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“…However, results have been underwhelming due to the tendency of MEK inhibitors to induce growth arrest but not apoptosis [26, 27]. …”

Section: Discussionmentioning

confidence: 99%

In pursuit of synergy: An investigation of the PI3K/mTOR/MEK co-targeted inhibition strategy in NSCLC

et al. 2016

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Clinical PI3K inhibition has been somewhat disappointing, due to both inadequate patient stratification and compensatory cell signalling through bypass mechanisms. As such, investigation of PI3K-MEK co-targeted inhibition has been recommended. With high mortality rates and a clear need for new therapeutic intervention strategies, non-small cell lung cancer (NSCLC) is an important setting to investigate the effectiveness of this approach.Here, 174 NSCLC tumours were screened for 150 mutations by Fluidigm technology, with 15 patients being profiled for phosphoprotein expression. The effects of GDC-0941 (a pan PI3K inhibitor), GDC-0980 (a dual PI3K/mTOR inhibitor) and GDC-0973 (a MEK inhibitor) alone and in combination were assessed in 3 NSCLC cell lines.PIK3CA was mutated in 5.17% of NSCLC patients. GDC-0941 and GDC-0980 treatment induced anti-proliferative and pro-apoptotic responses across all NSCLC cell lines, while GDC-0973 treatment induced only anti-proliferative responses. GDC-0980 and GDC-0973 combined treatment led to significant increases in apoptosis and synergistic reductions in proliferation across the panel of cell lines.This study found that the PI3K/MEK co-targeted inhibition strategy is synergistic in all 3 molecular subtypes of NSCLC investigated. Consequently, we would advocate clinical trials for NSCLC patients combining GDC-0980 and GDC-0973, each of which are separately under clinical investigation currently.

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Genomic classification of the RAS network identifies a personalized treatment strategy for lung cancer

Cited by 12 publications

References 69 publications

KRASoncogene in lung cancer: focus on molecularly driven clinical trials

KRASoncogene in lung cancer: focus on molecularly driven clinical trials

Activity of distinct growth factor receptor network components in breast tumors uncovers two biologically relevant subtypes

In pursuit of synergy: An investigation of the PI3K/mTOR/MEK co-targeted inhibition strategy in NSCLC

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