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Resistance to Anti-Cancer Therapeutics Targeting Receptor Tyrosine Kinases and Downstream Pathways pp 1–27Cite as

Resistance of Colorectal Tumors to Anti-EGFR Antibodies

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Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 15))

Abstract

Only a small fraction (10%) of genetically unselected patients with chemorefractory metastatic colorectal cancer benefits from the anti-EGFR antibodies cetuximab or panitumumab (‘primary’ or ‘de novo’ resistance). Further, almost all patients who initially respond become resistant over the course of treatment (‘secondary’ or ‘acquired’ resistance). Studies in cell lines, patient-derived tumorgrafts, and archival surgical specimens have identified many biomarkers of both primary and acquired resistance to anti-EGFR antibodies, and it is now evident that resistance mechanisms revolve around common genetic lesions and share analogous signaling traits. Here we discuss how resistance to the EGFR blockade is attained in colorectal cancer and elaborate on alternative therapeutic strategies that are now under development to improve response and contrast relapse.

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Abbreviations

BRAF:

v-Raf murine sarcoma viral oncogene homolog B1

CRC:

Colorectal cancer

ctDNA:

Circulating tumor DNA

EGFR/ErbB1/HER1:

Epidermal growth factor receptor

ERK:

Extracellular signal regulated kinase

HER2/neu/ERBB2:

V-ERB-B2 avian erythroblastic leukemia viral oncogene homolog 2

KRAS:

V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog

mCRC:

Metastatic colorectal cancer

MEK:

Mitogen-activated protein kinase kinase

moAbs:

Monoclonal Antibodies

NRAS:

Neuroblastoma RAS viral oncogene homolog

PIK3CA:

Phosphatidylinositol 3-kinase, catalytic, alpha

PTEN:

Phosphatase and tensin homolog

RR:

Response rate

RTKs:

Receptor Tyrosine kinases

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Acknowledgments

Work in the author’s laboratory is supported by AIRC, Associazione Italiana per la Ricerca sul Cancro—2010 Special Program Molecular Clinical Oncology 5 × 1000, project 9970— and AIRC Investigator Grant, project 18532; FPRC, Fondazione Piemontese per la Ricerca sul Cancro, Ministero della Salute 2011; ERA-NET TRANSCAN, project TACTIC.Clinical trials available at:NCT01085331: http://clinicaltrials.gov/ct2/show/NCT01085331?term=NCT01085331&rank=1NCT01390818: http://clinicaltrials.gov/ct2/results?term=NCT01390818&Search=SearchNCT02039336: http://clinicaltrials.gov/ct2/show/NCT02039336?term=NCT02039336&rank=1NCT01154335: http://clinicaltrials.gov/ct2/show/NCT01154335?term=colorectal+cancer&rank=33NCT01139138: http://clinicaltrials.gov/ct2/show/NCT01139138?term=colorectal+cancer&rank=67NCT01387880: http://clinicaltrials.gov/ct2/show/NCT01387880?term=everolimus+AND+colorectal+cancer&rank=2NCT00827684: http://clinicaltrials.gov/ct2/show/NCT00827684?term=everolimus+AND+colorectal+cancer&rank=9NCT02034981: http://clinicaltrials.gov/ct2/results?term=NCT02034981&Search=Search

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No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy

    Livio Trusolino

  2. Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute—FPO IRCCS, 10060 Candiolo, Torino, Italy

    Livio Trusolino & Simonetta M. Leto

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  1. Livio Trusolino
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  2. Simonetta M. Leto
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Correspondence to Livio Trusolino .

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Editors and Affiliations

  1. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    Yosef Yarden

  2. Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheeva, Israel

    Moshe Elkabets

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Trusolino, L., Leto, S.M. (2018). Resistance of Colorectal Tumors to Anti-EGFR Antibodies. In: Yarden, Y., Elkabets, M. (eds) Resistance to Anti-Cancer Therapeutics Targeting Receptor Tyrosine Kinases and Downstream Pathways. Resistance to Targeted Anti-Cancer Therapeutics, vol 15. Springer, Cham. https://doi.org/10.1007/978-3-319-67932-7_1

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