Blockade of EGFR and MEK Intercepts Heterogeneous Mechanisms of Acquired Resistance to Anti-EGFR Therapies in Colorectal Cancer

Misale, Sandra; Arena, Sabrina; Lamba, Simona; Siravegna, Giulia; Lallo, Alice; Hobor, Sebastijan; Russo, Mariangela; Buscarino, Michela; Lazzari, Luca; Sartore-Bianchi, Andrea; Bencardino, Katia; Amatu, Alessio; Lauricella, Calogero; Valtorta, Emanuele; Siena, Salvatore; Nicolantonio, Federica Di; Bardelli, Alberto

doi:10.1126/scitranslmed.3007947

Cited by 240 publications

(276 citation statements)

References 45 publications

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“…The fi nding that most of the mutations that emerge upon treatment involve genes that are direct members of the EGFR pathway ( EGFR, KRAS, NRAS, or BRAF ) indicates that to escape the perturbation, the cells must settle on a new balance, which is (has to be) again based on a certain level of EGFR signaling output. This hypothesis is supported by a biochemical analysis of cell models of colorectal cancer that developed resistance to EGFR blockade regardless of the gene/mutation that confers resistance; the net output was always sustained activation of MEK and ERK, thus defi ning an example of convergent evolution ( 76 ). and acquired resistance largely overlap.…”

Section: All Roads Lead To Romementioning

confidence: 69%

“…Colorectal cancer cell lines made resistant to cetuximab or panitumumab showed the concomitant presence of diverse genetic mechanisms; for instance, in one single resistant cell model, we were able to identify multiple KRAS mutations, together with NRAS -mutant clones as well ( 76 ). The genetic landscapes of cell models are generally considered molecularly homogeneous; however, these experiments suggest that the resistant population may arise upon the selection of multiple clones that were presumably already present at the beginning of the treatment.…”

Section: Mutations In Ras Genesmentioning

confidence: 84%

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

et al. 2014

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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.

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Section: All Roads Lead To Romementioning

confidence: 69%

Section: Mutations In Ras Genesmentioning

confidence: 84%

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

et al. 2014

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“…First, CRC tumors that acquire resistance to anti-EGFR therapy do not show the emergence of a single mutated clone, but typically the concomitant presence of diverse genetic abnormalities. 102 It is not yet known whether these molecular changes are exclusively due to a passive clonal selection mechanism or involve treatment-induced mutagenesis. Second, there is a marked overlap between molecular abnormalities associated with primary resistance (i.e.…”

Section: Tracking Resistance and Tailoring Therapiesmentioning

confidence: 99%

“…99 Amplification of KRAS and co-occurring amplifications, such as MET and ERBB2, are additional mechanisms of resistance to anti-EGFR therapies. [100][101][102] In this setting, serial analysis of ctDNA provides a valuable opportunity for early detection of molecular changes that potentially confer resistance, 47,[103][104][105] thereby enabling early treatment modification, which may prevent disease progression.…”

Section: Tracking Resistance and Tailoring Therapiesmentioning

confidence: 99%

Future perspectives of circulating tumor DNA in colorectal cancer

et al. 2017

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Tumor biopsy is currently the gold standard for diagnosis and in determining cell signaling pathways involved in the development of treatment resistance. However, there are major challenges with this technique, including the need for serial sampling to monitor treatment resistance, which is invasive and also has the potential for selection bias due to intra-tumoral and inter-tumoral heterogeneity. These challenges highlight the need for more effective methods for obtaining Tumor samples. Liquid biopsy analyzes genetic material or tumor cells shed into the blood from the primary tumor and metastatic sites and consequently provides a comprehensive, real-time picture of the tumor burden in an individual patient. Indeed, liquid biopsy has the potential to revolutionize cancer management. Here, we review recent studies on the potential clinical applications of liquid biopsy using circulating tumor DNA in colorectal cancer, including screening, diagnosis, detection of minimal residual disease after surgery, detection of recurrence, prognosis, predicting treatment response, monitoring tumor burden or response during treatment, and tracking resistance. We also discuss recent data demonstrating the utility of detecting KRAS-mutated circulating tumor DNA, both at diagnosis to determine an appropriate treatment strategy and during anti-epidermal growth factor receptor therapy to predict treatment resistance. The future integration of liquid biopsy into clinical practice is discussed, together with alternative approaches and key questions that need to be answered in future clinical studies before this technology can be implemented and used routinely.

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“…Several targeted therapeutic strategies designed to circumvent resistance driven by downstream pathway reactivation are being investigated in ongoing clinical trials that combine an anti-EGFR drug with other targeted therapies such as the HER2 inhibitor trastuzumab or MEK inhibitors (13,14). However, therapeutic strategies to overcome resistance mediated by mutations in EGFR are poorly characterized.…”

Section: Introductionmentioning

confidence: 99%

The First-in-class Anti-EGFR Antibody Mixture Sym004 Overcomes Cetuximab Resistance Mediated by EGFR Extracellular Domain Mutations in Colorectal Cancer

Sánchez-Martín

Bellosillo

Gelabert-Baldrich

et al. 2016

Clinical Cancer Research

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Purpose: Approved anti-EGFR antibodies cetuximab and panitumumab provide significant clinical benefit in patients with metastatic colorectal cancer (MCRC). However, patients ultimately develop disease progression, often driven by acquisition of mutations in the extracellular domain (ECD) of EGFR. Sym004 is a novel 1:1 mixture of two nonoverlapping anti-EGFR mAbs that recently showed promising clinical activity in a phase I trial in MCRC. Our aim was to determine the efficacy of Sym004 to circumvent cetuximab resistance driven by EGFR ECD mutations. Experimental Design: Functional studies were performed to assess drug–receptor binding as well as ligand-dependent activation of individual EGFR mutants in the presence of cetuximab, panitumumab, and Sym004. Cell viability and molecular effects of the drugs were assayed in cetuximab-resistant cell lines and in tumor xenograft models. Efficacy of Sym004 was evaluated in patients progressing to cetuximab that harbored EGFR mutation in the post-cetuximab tumor sample. Results: Contrary to cetuximab and panitumumab, Sym004 effectively bound and abrogated ligand-induced phosphorylation of all individual EGFR mutants. Cells resistant to cetuximab harboring mutations in EGFR maintained sensitivity to Sym004, which was consistent with an effective suppression of EGFR downstream signaling, translating into profound and sustained tumor regression in the xenograft model. As proof-of-principle, a patient with a tumor harboring an EGFR mutation (G465R) following cetuximab therapy benefited from Sym004 therapy. Conclusions: Sym004 is an active drug in MCRC resistant to cetuximab/panitumumab mediated by EGFR mutations. EGFR mutations are potential biomarkers of response to Sym004 to be evaluated in ongoing large clinical trials. Clin Cancer Res; 22(13); 3260–7. ©2016 AACR.

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Blockade of EGFR and MEK Intercepts Heterogeneous Mechanisms of Acquired Resistance to Anti-EGFR Therapies in Colorectal Cancer

Cited by 240 publications

References 45 publications

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

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

Future perspectives of circulating tumor DNA in colorectal cancer

The First-in-class Anti-EGFR Antibody Mixture Sym004 Overcomes Cetuximab Resistance Mediated by EGFR Extracellular Domain Mutations in Colorectal Cancer

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