Impact of specific mutant KRAS on clinical outcome of EGFR-TKI-treated advanced non-small cell lung cancer patients with an EGFR wild type genotype

Metro, Giulio; Chiari, Rita; Duranti, Simona; Siggillino, Annamaria; Fischer, Matthias; Giannarelli, Diana; Ludovini, Vienna; Bennati, Chiara; Marcomigni, Luca; Baldi, A.; Giansanti, Michele; Minotti, Vincenzo; Crinò, Lucio

doi:10.1016/j.lungcan.2012.06.005

Cited by 62 publications

(54 citation statements)

References 33 publications

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“…Oncogenic mutations in RAS genes cluster either at codon 12, 13, or 61 and recent reports suggest specific cellular signaling may result from activation at different hotspots. 34 Therefore, the apparent NRAS specificity could be confounded by hotspot bias if 1 mutant codon in NRAS conferred resistance and mutation within that codon was absent from KRAS mutants in this data set. The observed effects of NRAS mutation in the present study might have been explained by the fact that codon 61 is mutated more frequently in NRAS than in KRAS 10 ; however, as summarized in supplemental Table 8, this possibility is not supported by the current data set.…”

Section: Mutation Status Impacts Subsequent Drug Responsementioning

confidence: 93%

Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy

Mulligan

Lichter

Bacco

et al. 2014

Blood

109

101

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Key Points• A high frequency of RAS/RAF mutations and recurrent mutations in PDGFRA and JAK3 were found in relapsed multiple myeloma patients.• Patients with NRAS, but not KRAS, mutation exhibited significantly reduced sensitivity to bortezomib but not high-dose dexamethasone.Various translocations and mutations have been identified in myeloma, and certain aberrations, such as t(4;14) and del17, are linked with disease prognosis. To investigate mutational prevalence in myeloma and associations between mutations and patient outcomes, we tested a panel of 41 known oncogenes and tumor suppressor genes in tumor samples from 133 relapsed myeloma patients participating in phase 2 or 3 clinical trials of bortezomib. DNA mutations were identified in 14 genes. BRAF as well as RAS genes were mutated in a large proportion of cases (45.9%) and these mutations were mutually exclusive. New recurrent mutations were also identified, including in the PDGFRA and JAK3 genes. NRAS mutations were associated with a significantly lower response rate to single-agent bortezomib (7% vs 53% in patients with mutant vs wildtype NRAS, P 5 .00116, Bonferroni-corrected P 5 .016), as well as shorter time to progression in bortezomib-treated patients (P 5 .0058, Bonferroni-corrected P 5 .012). However, NRAS mutation did not impact outcome in patients treated with high-dose dexamethasone. KRAS mutation did not reduce sensitivity to bortezomib or dexamethasone. These findings identify a significant clinical impact of NRAS mutation in myeloma and demonstrate a clear example of functional differences between the KRAS and NRAS oncogenes. (Blood. 2014; 123(5):632-639)

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Section: Mutation Status Impacts Subsequent Drug Responsementioning

confidence: 93%

Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy

Mulligan

Lichter

Bacco

et al. 2014

Blood

109

101

View full text Add to dashboard Cite

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“…Similarly, in pancreatic cancer, KRAS mutations (codon 12 or 13) are associated with worse prognosis (32), and in NSCLC, patients with advanced KRAS-mutant cancer have a shorter survival compared with those with EGFR-mutant or EGFR/KRAS wild-type (WT) cancers (33,34). In addition, KRAS mutations predict for resistance to treatment with EGFR tyrosine kinase inhibitors (17,35,36). Ihle and colleagues reported that patients with NSCLC whose tumors had either KRAS-G12C or KRAS-G12V mutations had worse progression-free survival (PFS) compared with patients whose tumors had other KRASmutant tumors or lacked KRAS mutations (17).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: The Basis for Rational Combination Using MEK Inhibitors in KRAS-Mutant Cancers

Okumura¹

2014

Clinical Cancer Research

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Mutations in RAS oncogenes are frequently observed in human cancers, and the mutations result in activation of the RAS-RAF-MEK-ERK pathway, leading to cell proliferation and survival. The pathway is, therefore, a potent therapeutic target in the RAS-mutant cancers. MEK inhibitors can specifically block the pathway and are one of the key types of drugs for the treatment of the RAS-mutant cancers. As RAS proteins activate other downstream signaling proteins in addition to the RAS-RAF-MEK-ERK pathway, combination therapeutic approaches with MEK inhibitors are also being evaluated. Moreover, MEK inhibitors can arrest cancer cells in G 1 phase and repress prosurvival Bcl2 family proteins such as MCL1 and BCL2/BCLXL, and increase expression of Bim, a proapoptotic BH3-only family protein. This mechanism may explain the efficacy of the combination of MEK inhibitors with cytotoxic agents or other targeted inhibitors. A better understanding of the pathway will help us with development of rational combinations for the treatment of the RAS-mutant cancers.

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“…Until 2010, KRAS mutations were considered negative predictive factors in advanced NSCLC patients treated by inhibitors of the tyrosine kinase domain (TKI) of the EGFR, according to the results of two meta-analyses evaluating both erlotinib and gefitinib [5,19,20]. When focusing exclusively on EGFR wild-type cases, KRAS mutations might not keep this negative predictive value [18,[21][22][23]. To the best of our knowledge, data related to clinical benefits of bevacizumab according to KRAS mutational status are lacking.…”

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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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Impact of specific mutant KRAS on clinical outcome of EGFR-TKI-treated advanced non-small cell lung cancer patients with an EGFR wild type genotype

Cited by 62 publications

References 33 publications

Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy

Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy

Molecular Pathways: The Basis for Rational Combination Using MEK Inhibitors in KRAS-Mutant Cancers

KRASoncogene in lung cancer: focus on molecularly driven clinical trials

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