- Short communication
- Open Access
Colon cancer-derived oncogenic EGFR G724S mutant identified by whole genome sequence analysis is dependent on asymmetric dimerization and sensitive to cetuximab
- Jeonghee Cho†1, 2, 3, 4Email author,
- Adam J Bass†1, 2, 5,
- Michael S Lawrence5,
- Kristian Cibulskis5,
- Ahye Cho3, 4,
- Shi-Nai Lee6,
- Mai Yamauchi1,
- Nikhil Wagle1, 2,
- Panisa Pochanard1, 2,
- Nayoung Kim3, 4,
- Angela K J Park3, 4,
- Jonghwa Won6,
- Hyung-Suk Hur6,
- Heidi Greulich1, 5, 7,
- Shuji Ogino1,
- Carrie Sougnez5,
- Douglas Voet5,
- Josep Tabernero8,
- Jose Jimenez9,
- Jose Baselga10,
- Stacey B Gabriel5,
- Eric S Lander5,
- Gad Getz5,
- Michael J Eck11, 12,
- Woong-Yang Park3, 4 and
- Matthew Meyerson1, 2, 5, 12Email author
© Cho et al.; licensee BioMed Central Ltd. 2014
- Received: 7 February 2014
- Accepted: 23 May 2014
- Published: 4 June 2014
Inhibition of the activated epidermal growth factor receptor (EGFR) with either enzymatic kinase inhibitors or anti-EGFR antibodies such as cetuximab, is an effective modality of treatment for multiple human cancers. Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while, paradoxically, anti-EGFR antibodies are more effective in colon and head and neck cancers where EGFR mutations occur less frequently. In colorectal cancer, anti-EGFR antibodies are routinely used as second-line therapy of KRAS wild-type tumors. However, detailed mechanisms and genomic predictors for pharmacological response to these antibodies in colon cancer remain unclear.
We describe a case of colorectal adenocarcinoma, which was found to harbor a kinase domain mutation, G724S, in EGFR through whole genome sequencing. We show that G724S mutant EGFR is oncogenic and that it differs from classic lung cancer derived EGFR mutants in that it is cetuximab responsive in vitro, yet relatively insensitive to small molecule kinase inhibitors. Through biochemical and cellular pharmacologic studies, we have determined that cells harboring the colon cancer-derived G719S and G724S mutants are responsive to cetuximab therapy in vitro and found that the requirement for asymmetric dimerization of these mutant EGFR to promote cellular transformation may explain their greater inhibition by cetuximab than small-molecule kinase inhibitors.
The colon-cancer derived G719S and G724S mutants are oncogenic and sensitive in vitro to cetuximab. These data suggest that patients with these mutations may benefit from the use of anti-EGFR antibodies as part of the first-line therapy.
- Epidermal Growth Factor Receptor
- Epidermal Growth Factor Receptor Mutation
- Epidermal Growth Factor Receptor Gene
- Epidermal Growth Factor Receptor Signaling
Activation of the epidermal growth factor receptor (EGFR) oncoprotein, a member of the ErbB family of receptor tyrosine kinases, is among the most common oncogenic driving events in human cancer. Genomic mechanisms for activating the EGFR gene include nucleotide substitutions and in-frame insertions/deletions of the kinase domain in lung adenocarcinoma and papillary thyroid carcinomas, and multi-exonic deletions (exons 2 through 7: EGFR variant III or vIII), nucleotide substitutions of the extracellular domain and carboxyl terminal deletions in glioblastoma[2–6]. EGFR is also activated by high-copy amplifications in many epithelial cancer types, prominently in lung and upper gastrointestinal carcinomas as well as glioblastoma and head and neck cancer[7–10]. Furthermore, EGFR protein is over-expressed in many cancers even without evidence of focused genomic alteration, as observed in many cases of colorectal carcinoma where EGFR kinase domain mutations were found in only 3 out of 224 cases, 1.3% subjected to whole exome sequencing[11, 12]. Given the elevated expression and genomic alterations present in EGFR, multiple cancer therapies have targeted EGFR, as both its kinase activity and its dependence on extracellular ligand signaling have rendered EGFR vulnerable to therapeutic intervention. FDA-approved EGFR targeted inhibitors include the low-molecular-weight ATP-competitive kinase inhibitors, such as gefitinib and erlotinib, and humanized monoclonal antibodies directed against the extracellular domain, notably cetuximab and panitumumab. Although high-level expression of EGFR ligands and/or increased EGFR gene copy numbers may be predictive markers for antitumor response by cetuximab in colon cancer[14–16], and patients with RAS driven cancers are known not to benefit from cetuximab treatment, a clear molecular explanation of cancer response to cetuximab has remained elusive.
Colorectal adenocarcinoma has been a classic model to study the progressive accumulation of genomic lesions leading to cellular transformation. Key genomic features of these tumors involve inactivation of tumor suppressors such as APC, TP53 and SMAD4 and mutational activation of oncogenes including KRAS, NRAS, BRAF and PIK3CA. Given the role of cetuximab in therapy of these cancers, initial efforts to identify activating EGFR mutations identified few such events, though potentially activating events such as G719S were seen. More recent reports have also identified potentially mutations of ERBB3 and amplifications and mutations of ERBB2 in CRC[12, 20]. We have previously reported whole genome sequence analysis of nine colorectal carcinoma/normal pairs,leading to the identification of activating translocations of TCF7L2 and of the association of Fusobacterium nucleatum with colorectal carcinomas[21, 22]. Here, we report genomic analysis of a tenth anonymized case of colorectal carcinoma. Whole genome sequencing was performed on the genomic DNA from colorectal carcinoma tissue and adjacent non-neoplastic colonic tissue to a median coverage of 32.5x and 34.2x coverage, respectively, with 86.8% of the genome sequenced to adequate depth for mutation calling.
The absence of both KRAS and BRAF mutations are common features seen in colorectal cancers that are responsive to cetuximab[25, 26], thus making the EGFR mutation in this case of particular interest. The somatic G724S mutation in EGFR occurs at the final glycine of the GxGxxG nucleotide-binding motif that is essential for ATP binding and is conserved among all protein kinases (Figure 1C)[27, 28]. Substitution of EGFR G719, the first residue of this motif, to serine, cysteine, or alanine, has been observed in lung adenocarcinomas (~1%), and one G719S mutant and four G724S mutants have been reported in colorectal carcinomas that were sequenced for EGFR (Figure 1C)[18, 29] (COSMIC database). In addition, these EGFR mutations were found to be mutually exclusive with well known KRAS, BRAF and PIK3CA oncogenic driver mutations, demonstrating their potential role in tumorigenesis (COSMIC database).
To determine whether the G724S mutant is oncogenic and to evaluate its pharmacologic sensitivity, we generated this mutant in vitro and retrovirally transduced it into NIH-3T3 cells. While wild-type EGFR expressing NIH-3T3 cells form colonies in soft agar only in the presence of ligand, NIH-3T3 cells that express EGFR G724S form colonies in the absence of exogenous ligand, as do the lung and colon cancer-derived G719S mutants (Additional file1: Figure S2A). Furthermore, both G719S and G724S mutants undergo constitutive tyrosine-phosphorylation, which is further increased by EGF treatment, whereas phosphorylation of wild-type EGFR requires induction by EGF (Additional file1: Figure S2B). These data demonstrate that colon-cancer derived G719S and G724S mutants are oncogenically active in the absence of ligand stimulation.
In order to further examine the efficacy of cetuximab, we expanded our studies by generating xenograft mouse models with either SW48 or HCT8 colon cancer cells, which harbor either EGFR G719S or KRAS G13D mutation, respectively. Here, we found that consistent with in vitro response (Additional file1: Figure S3B), cetuximab treatment dramatically suppressed tumor formation driven by SW48 cells (Figure 2B), suggesting the anti-tumor effect of cetuximab against tumors harboring EGFR G719S mutant. In contrast, cetuximab treatment was ineffective for the tumors driven by HCT8, which is consistent with the previous findings that KRAS-mutant tumors are insensitive to cetuximab (Figure 2C). Taken together, we found that G719S and G724S mutants are oncogenic in the absence of ligand stimulation and effectively respond to cetuximab in vivo and in vitro.
Recently, we reported that a subset of lung cancer-derived oncogenic EGFR mutants such as L858R require asymmetric dimerization for biochemical activation and oncogenic transforming activity, meaning that their oncogenic ability depend on formation of an EGFR homodimer in which two distinct regions of the two molecule dimerize. By contrast, we showed that other EGFR mutants are oncogenic without the requirement for dimerization, including the gefitinib-resistant exon 20 insertion mutant and the T790M mutant. Furthermore, we found that dimerization-dependent L858R mutant shows a dramatic response to cetuximab, whereas tumors driven by dimerization-independent mutants such as T790M are resistant to the antibody, suggesting that there is a close correlation between dimerization dependency of lung cancer-derived oncogenic mutant EGFR and pharmacological effects of cetuximab. Given that colon cancer-derived G719S and G724S mutants are sensitive to cetuximab, we sought to examine whether oncogenic potential of these mutants are dependent on the asymmetric dimerization like lung cancer-derived L858R mutant.
To test the hypothesis that cetuximab sensitivity of G719S and G724S mutants is a function of their dimerization dependence, we generated G719S and G724S mutants with compound substitution mutations at the dimerization interface in the N-lobe or C-lobe that disrupt the asymmetric dimerization of EGFR. Specifically, we generated epitope-tagged EGFR expression constructs that combined a receiver-impairing mutation (L704N) and/or an activator-impairing mutation (I941R) with oncogenic G719S and G724S mutants. The single or compound EGFR mutants were expressed in NIH-3T3 cells by retroviral transduction, and the EGFR mutant-expressing cells were assayed for their ability to grow in soft agar. In this system, the transforming ability of dimerization-dependent mutants is predicted to be abolished by cis mutation of the L704 or I941 mutations. Furthermore, co-expression of the L704N and I941R mutant forms, in contrast, is predicted to restore transforming ability that is dimerization-dependent, because the two mutant forms can heterodimerize. Therefore, this experiment allows us to test whether specific EGFR kinase domain mutants can induce cellular transformation in a dimerization dependent or independent fashion.
In summary, our findings suggest that EGFR mutation may underlie at least some cases of cetuximab responsiveness in colorectal carcinoma. While EGFR mutation has historically been believed to be rare in colorectal carcinomas, whole exome sequencing published through The Cancer Genome Atlas identified somatic non-synonymous coding EGFR mutations in 10 of 224 colorectal carcinoma cases (or 4.5%). While many such mutations may be passenger alterations that do not activate EGFR signaling, these results do speak to the potential for mutational activation of EGFR to result in susceptibility to anti-EGFR antibodies in a small fraction of CRC cases. Indeed, the recent demonstration of secondary somatic mutation in the EGFR extracellular domain conferring acquired resistance to cetuximab is consistent with attribution of responses to cetuximab to EGFR blockade. Anti-EGFR therapy in metastatic colorectal cancer has been reserved for second-line therapy after failure of initial empiric chemotherapy but is now increasingly also used as part of first-line therapy for RAS wild-type patients. As genomic diagnostics enter into routine clinical practice, patients whose CRCs harbor potentially oncogenic EGFR mutations will be identified, including those at codons 719 and 724. These results suggest that in such patients, therapeutic approaches utilizing EGFR-directed antibody as part of their initial therapy should be evaluated given the greater potential dependence on EGFR signaling in these patients.
We would like to thank all Meyerson lab members for thoughtful discussion. These works were in part supported by NCI R01 CA116020 (MM and MJE) and Samsung Medical Center intramural grant SGI-13-15 (JC).
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