Resistance of Colorectal Tumors to Anti-EGFR Antibodies

Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (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.

Keywords

Colorectal cancer Epidermal growth factor receptor Mitogen-activated protein kinase kinase Drug resistance 

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

Notes

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

Conflict of Interest

No potential conflicts of interest were disclosed.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of OncologyUniversity of Torino Medical SchoolTorinoItaly
  2. 2.Laboratory of Translational Cancer MedicineCandiolo Cancer Institute—FPO IRCCSTorinoItaly

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