TY - JOUR
T1 - Mechanisms of innate and acquired resistance to anti-EGFR therapy
T2 - A review of current knowledge with a focus on rechallenge therapies
AU - Parseghian, Christine M.
AU - Napolitano, Stefania
AU - Loree, Jonathan M.
AU - Kopetz, Scott
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Innate and acquired resistance to anti-EGFR therapy (EGFRi) is a major limitation in the treatment of metastatic colorectal cancer (mCRC). Although RAS genes are the most commonly mutated innate and acquired oncogenes in cancer, there are a number of other mechanisms that limit the effectiveness of EGFRi. Patients with innate resistance have been found to contain BRAFV600E mutations, and possibly MET, MEK, PIK3CA, PTEN, and HER2 alterations. Meanwhile, BRAFV600E mutations may also be involved in acquired resistance to EGFRi, in addition to EGFR ectodomain mutations, MET alterations, and possibly HER2 amplification. In addition, paracrine effects and cell-fate mechanisms of resistance are being increasingly described as contributing to acquired resistance. Utilization of circulating tumor DNA has been paramount in monitoring the dynamic nature of acquired resistance and has helped to guide treatment decisions, particularly in the EGFRi rechallenge setting. Herein, we provide an in-depth review of EGFRi-resistance mechanisms and describe the current therapeutic landscape in the hopes of identifying effective rechallenge strategies.
AB - Innate and acquired resistance to anti-EGFR therapy (EGFRi) is a major limitation in the treatment of metastatic colorectal cancer (mCRC). Although RAS genes are the most commonly mutated innate and acquired oncogenes in cancer, there are a number of other mechanisms that limit the effectiveness of EGFRi. Patients with innate resistance have been found to contain BRAFV600E mutations, and possibly MET, MEK, PIK3CA, PTEN, and HER2 alterations. Meanwhile, BRAFV600E mutations may also be involved in acquired resistance to EGFRi, in addition to EGFR ectodomain mutations, MET alterations, and possibly HER2 amplification. In addition, paracrine effects and cell-fate mechanisms of resistance are being increasingly described as contributing to acquired resistance. Utilization of circulating tumor DNA has been paramount in monitoring the dynamic nature of acquired resistance and has helped to guide treatment decisions, particularly in the EGFRi rechallenge setting. Herein, we provide an in-depth review of EGFRi-resistance mechanisms and describe the current therapeutic landscape in the hopes of identifying effective rechallenge strategies.
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U2 - 10.1158/1078-0432.CCR-19-0823
DO - 10.1158/1078-0432.CCR-19-0823
M3 - Review article
C2 - 31263029
AN - SCOPUS:85074766461
SN - 1078-0432
VL - 25
SP - 6899
EP - 6908
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -