KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience

Cutsem, Éric Van; Làng, István; D'Haens, G.; Moiseyenko, Vladimir; Załuski, J.; Folprecht, Gunnar; Tejpar, Sabine; Kisker, Oliver; Stroh, Christopher; Rougier, Philippe

doi:10.1200/jco.2008.26.15_suppl.2

Cited by 282 publications

(167 citation statements)

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“…Interestingly, most studies investigating cetuximab have not shown a clear association between EGFR expression and the therapeutic response (16). Moreover, whether negative predictors of responses such as those resulting from K-RAS mutations in colorectal cancer (17,18) could be applied to lung cancer must be confirmed.…”

Section: Discussionmentioning

confidence: 99%

Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response

Choi

Ryu

Kim

et al. 2010

Molecular Cancer Research

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Several studies have shown solid evidence for the potential value of targeting epidermal growth factor receptor (EGFR) signaling to enhance the antitumor activity of radiation. However, therapeutic resistance has emerged as an important clinical issue. Here, we investigated whether strategies for targeting EGFR-associated downstream signaling would radiosensitize a panel of non-small cell lung cancer cell lines. Inhibition of K-RAS using RNA interference attenuated downstream signaling and increased radiosensitivity of A549 and H460 cells, whereas inhibition of EGFR did not. A549 cells harboring a K-RAS mutation at codon V12 were radiosensitized by small interfering RNA (siRNA) targeting this codon. H460 cells having mutation at codon V61 was radiosensitized by siRNA targeting of this mutation. K-RAS siRNA did not radiosensitize H1299 cells possessing wild-type K-RAS. Inhibition of the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin pathway led to significant radiosensitization of the two cell lines, whereas selective inhibition of extracellular signal-regulated kinase signaling did not. Inhibitors targeting the PI3K-AKT-mTOR pathway also abrogated G 2 arrest following irradiation and induced γH2AX foci formation. A dual inhibitor of class I PI3K and mammalian target of rapamycin effectively increased the radiosensitivity of A549 and H460 cells. Inhibition of PI3K-AKT signaling was associated with the downregulation of DNA-PKs. Although apoptosis was the primary mode of cell death when cells were pretreated with LY294002 or AKT inhibitor VIII, cells pretreated with rapamycin or PI-103 showed mixed modes of cell death, including apoptosis and autophagy. Our results suggest possible mechanisms for counteracting EGFR prosurvival signaling implicated in radioresistance and offer an alternative strategy for overcoming resistance to EGFR inhibitors used in combination with irradiation.

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Section: Discussionmentioning

confidence: 99%

Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response

Choi

Ryu

Kim

et al. 2010

Molecular Cancer Research

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“…These data suggest that the presence of KRAS mutations may predict a poor response to gefitinib and erlotinib in patients with NSCLC, although RRs between tumors with and without KRAS mutations did not reach statistical significance in this study (Pao et al, 2005). In contrast, the presence of KRAS mutations is an established predictor of nonresponsiveness to cetuximab in patients with metastatic colorectal cancer and is associated with significant decreases in time to progression, PFS and OS (Lievre et al, 2006;Di Fiore et al, 2007;de Reynies et al, 2008;De Roock et al, 2008;Van Cutsem et al, 2008). The validation of KRAS mutations as a marker of natural resistance to EGFR inhibitors in lung adenocarcinoma will require both retrospective analyses of large randomized studies (for example, the FLEX study of cetuximab) and data from large prospective studies with erlotinib.…”

Section: Prognostic Versus Predictive Biomarkersmentioning

confidence: 67%

Individualized therapy in non-small-cell lung cancer: future versus current clinical practice

Pérez-Soler

2009

Oncogene

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“…The clinical response rate to treatment with FOLFOX/ FOLFIRI + molecularly targeted drugs is between 70 and 80% (12)(13)(14). First-line therapy with FOLFOX/FOLFIRI + molecularly targeted drugs should allow more appropriate selection of treatment (including conversion therapy) and lead to better prognoses in symptom-free cases.…”

Section: Discussionmentioning

confidence: 99%

Good response to leucovorin and fluorouracil plus oxaliplatin and cetuximab therapy in a patient with metastatic ascending colon cancer harboring a KRAS p.G13D mutation

Ochiai¹,

Nishimura²,

Watanabe³

et al. 2011

Oncology Letters

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Abstract. The effectiveness of cetuximab (Cmab) against KRAS p.G13D mutant-type tumors has been reported. In this study, we report a case of metastatic ascending colon cancer harboring a KRAS p.G13D mutation in a 65-year-old female. Considering the absence of symptoms and the post-operative risk of respiratory system complications due to multiple lung metastases, particularly at the entrance to the left main bronchus, anticancer drug therapy was selected as first-line therapy. With informed consent, FOLFOX4 [folinic acid (FOL), fluorouracil (F) plus oxaliplatin (OX)] + Cmab therapy was administered as preoperative chemotherapy. A good preoperative response was obtained to the chemotherapy, with a metastatic lesion disappearing from the entrance to the left main bronchus. Subsequent resection was performed successfully with no post-operative complications. Although a histopathological examination of the resected tissue specimen revealed residual cancer cells, it also showed the marked efficacy of the chemotherapy regimen used. In this study, we describe a case of metastatic ascending colon cancer harboring a KRAS p.G13D mutation in which the patient responded well to first-line therapy with FOLFOX4 + Cmab.

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KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience

Cited by 282 publications

References 0 publications

Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response

Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response

Individualized therapy in non-small-cell lung cancer: future versus current clinical practice

Good response to leucovorin and fluorouracil plus oxaliplatin and cetuximab therapy in a patient with metastatic ascending colon cancer harboring a KRAS p.G13D mutation

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