Loading
Bowel cancers that respond to cetuximab almost always stop responding within a year. This paper showed why: KRAS-mutant cells take over, and their DNA shows up in the blood months before a scan changes.
Molecular alterations of KRAS, in most instances point mutations, were shown to be causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expressing mutant KRAS under the control of its endogenous promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combined inhibition of EGFR and MEK. Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 6 of 10 cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression.
It made acquired resistance a measurable, plasma-readable event, and it is the origin of anti-EGFR rechallenge strategies guided by ctDNA clearance of the resistant clone.
Shares Cell-free DNA (cfDNA), Panitumumab, Clonal evolution & minimal residual disease, Nature.
Shares Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Andrea Sartore-Bianchi, Salvatore Siena, Istituto di Candiolo IRCCS (FPO).
Shares Rona Yaeger, Cetuximab, RAS / RAF / MEK / ERK (MAPK), EGFR.
Shares Panitumumab, Cetuximab, Circulating tumour DNA (ctDNA), EGFR.
Shares Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Andrea Sartore-Bianchi, Salvatore Siena, Istituto di Candiolo IRCCS (FPO).
Shares Salvatore Siena, Panitumumab, RAS / RAF / MEK / ERK (MAPK), EGFR.
Shares Panitumumab, Circulating tumour DNA (ctDNA), EGFR, KRAS.
Shares Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Andrea Sartore-Bianchi, Salvatore Siena, Colorectal cancer.