Expansion of preexisting KRAS-mutant subclones drives resistance to cetuximab and panitumumab.
Major finding: Expansion of preexisting KRAS-mutant subclones drives resistance to cetuximab and panitumumab.
Clinical relevance: KRAS-mutant cells can be detected noninvasively prior to radiographic progression.
Impact: Early initiation of combinatorial EGFR and MEK inhibition may delay or reverse drug resistance.
A subset of KRAS–wild-type metastatic colorectal cancers initially responds to cetuximab and panitumumab, monoclonal antibodies that block the epidermal growth factor receptor (EGFR), but ultimately develop resistance within 5 to 6 months. Misale and colleagues continuously treated KRAS, BRAF, and PIK3CA–wild-type colorectal cancer cell lines with cetuximab and observed that cells that developed resistance had selectively acquired amplifications or activating mutations of KRAS that were sufficient to induce cetuximab resistance in vitro. Deep sequencing of tumor biopsies from patients with colorectal cancer that had developed cetuximab or panitumumab resistance revealed the emergence of KRAS mutations in 7 of 11 tumors, whereas tumors that had not been treated with anti-EGFR antibodies did not develop KRAS mutations. Additionally, analysis of KRAS allelic frequency in plasma samples from patients treated with cetuximab showed that KRAS mutations in circulating tumor DNA could be identified as early as 10 months before disease progression was confirmed by radiologic assessment. Diaz and colleagues also noted the development of KRAS mutations in the serially acquired serum samples of 9 of 24 patients receiving panitumumab prior to or concurrent with radiographic progression. Mathematical models based on the circulating tumor DNA data indicated that tumor cells harboring KRAS mutations were present in a subclonal population prior to panitumumab treatment and would become observable in circulating DNA an average of 22 weeks after initiation of treatment, suggesting that the time to disease recurrence is the time it takes preexisting KRAS-mutant subclones to repopulate the tumor. Collectively, these findings establish that noninvasive detection of KRAS mutations in the serum may be an early indicator of acquired resistance to anti-EGFR antibody therapy and suggest that combined treatment with inhibitors targeting downstream KRAS effectors such as MEK may be able to reverse or delay cetuximab or panitumumab resistance.
Diaz LA, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 2012 Jun 13 [Epub ahead of print].
- ©2012 American Association for Cancer Research.