The S492R EGFR ectodomain mutation is never detected in KRAS wild-type colorectal carcinoma before exposure to EGFR monoclonal antibodies

Esposito, Claudia; Rachiglio, Anna Maria; Porta, Maria Libera La; Sacco, Alessandra; Roma, Cristin; Iannaccone, Alessia; Tatangelo, Fabiana; Forgione, Laura; Pasquale, Raffaella; Barbaro, Americo; Botti, Gerardo; Ciardiello, Fortunato; Normanno, Nicola

doi:10.4161/cbt.26340

Cited by 49 publications

(46 citation statements)

References 23 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, similar to our results, Misale and colleagues (15) were unable to detect the LIM 1215 cetuximab-resistant KRAS G12R mutation in the LIM 1215 parental cells implying that this mutation was acquired during treatment. Moreover, the EGFR S492 gene mutation that was demonstrated to be responsible for the acquisition of cetuximab resistance was not found in metastatic colorectal cancer patients before anti-EGFR treatment (33,44).…”

Section: Discussionmentioning

confidence: 99%

Maintenance Treatment with Cetuximab and BAY86-9766 Increases Antitumor Efficacy of Irinotecan plus Cetuximab in Human Colorectal Cancer Xenograft Models

Troiani

Napolitano

Martini

et al. 2015

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: The use of cetuximab in the treatment of metastatic colorectal cancer is limited by development of resistance.Experimental Design: We have investigated in three models of highly epidermal growth factor receptor (EGFR)-dependent colorectal cancer xenografts, the effect of maintenance therapy with different kinase inhibitors alone or in combination with cetuximab, after cytotoxic treatment induction with irinotecan plus cetuximab.Results: SW48, LIM 1215, and GEO colorectal cancer cell lines were engrafted into nude mice and treated for 3 weeks with irinotecan and/or cetuximab. The combined treatment induced a significant reduction of tumor size. A subsequent experiment was performed in all three xenograft models in which after an induction treatment with irinotecan plus cetuximab, mice were randomly assigned to one of the following treatments: control, cetuximab, regorafenib, a selective PIK3CA inhibitor (PIK3CAi), a selective MEK inhibitor (MEKi), and /or the combination of each inhibitor with cetuximab. The cetuximab plus MEKi treatment determined the best antitumor activity with suppression of tumor growth. This effect was prolonged for 13 to 15 weeks after cessation of therapy and was accompanied by prolonged survival. Antitumor activity was accompanied by inhibition of the MAPK and MEK pathways. Moreover, in the cetuximab plus MEKi-treated SW48 xenograft group, KRAS mutations as a mechanism of acquired resistance were detected in 25% of cases compared with 75% KRAS mutations in the MEKi-treated group.Conclusions: A possible strategy to prevent and/or overcome resistance to anti-EGFR inhibitors in metastatic colorectal cancer is a maintenance therapy with cetuximab plus MEKi after an initial treatment with irinotecan plus cetuximab.

show abstract

Section: Discussionmentioning

confidence: 99%

Maintenance Treatment with Cetuximab and BAY86-9766 Increases Antitumor Efficacy of Irinotecan plus Cetuximab in Human Colorectal Cancer Xenograft Models

Troiani

Napolitano

Martini

et al. 2015

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Two recent reports even suggested that the recurrent S492R mutation is acquired through exposure to EGFR monoclonal antibodies rather than being a primary event in carcinogenesis [79,80]. An increase in EGFR gene copy number, mainly due to polysomy of chromosome 7, has also been reported.…”

Section: Genetic Alterations In the Pi3k/akt Pathwaymentioning

confidence: 95%

Portrait of the PI3K/AKT pathway in colorectal cancer

Danielsen¹,

Eide²,

Nesbakken³

et al. 2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

222

200

View full text Add to dashboard Cite

“…The S492R allele has never been detected to date in untreated colorectal cancer ( 86 ) and is apparently found only in colorectal cancer samples from patients who have been previously exposed to cetuximab. This is consistent with the hypothesis that this allele evolves as cells strive to evade the EGFR blockade imposed by the monoclonal antibody cetuximab, and accordingly remain sensitive to panitumumab, which binds to a different EGFR epitope located on the extracellular domain of EGFR.…”

Section: The Primary = Secondary Rule Has Exceptionsmentioning

confidence: 99%

Resistance to Anti-EGFR Therapy in Colorectal Cancer: From Heterogeneity to Convergent Evolution

et al. 2014

View full text Add to dashboard Cite

The EGFR-targeted antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancers. Mutations in KRAS , NRAS, and BRAF and amplification of ERBB2 and MET drive primary ( de novo ) resistance to anti-EGFR treatment. Recently, the emergence of alterations in the same genes was detected in patients who responded to EGFR blockade and then relapsed. These results illuminate a striking overlap between genes that, when mutated, drive primary and secondary resistance to anti-EGFR antibodies. Remarkably, although the mechanisms of resistance are genetically heterogeneous, they biochemically converge on key signaling pathways. This knowledge is being translated in the rational design of additional lines of therapy.Signifi cance: Anti-EGFR-targeted therapies are used for the treatment of metastatic colorectal cancer. Molecular heterogeneity impairs their effi cacy by fuelling de novo and acquired resistance. In this review, we highlight how genetically distinct resistance mechanisms biochemically converge on a limited number of signaling pathways that can be therapeutically intercepted.

show abstract

The S492R EGFR ectodomain mutation is never detected in KRAS wild-type colorectal carcinoma before exposure to EGFR monoclonal antibodies

Cited by 49 publications

References 23 publications

Maintenance Treatment with Cetuximab and BAY86-9766 Increases Antitumor Efficacy of Irinotecan plus Cetuximab in Human Colorectal Cancer Xenograft Models

Maintenance Treatment with Cetuximab and BAY86-9766 Increases Antitumor Efficacy of Irinotecan plus Cetuximab in Human Colorectal Cancer Xenograft Models

Portrait of the PI3K/AKT pathway in colorectal cancer

Resistance to Anti-EGFR Therapy in Colorectal Cancer: From Heterogeneity to Convergent Evolution

Contact Info

Product

Resources

About