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. 2008 Mar 15;68(6):1953-61.
doi: 10.1158/0008-5472.CAN-07-5659.

"VSports" PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab

Minaxi Jhawer  1 , Sanjay Goel, Andrew J Wilson, Cristina Montagna, Yi-He Ling, Do-Sun Byun, Shannon Nasser, Diego Arango, Joongho Shin, Lidija Klampfer, Leonard H Augenlicht, Roman Perez-Soler, John M Mariadason
Affiliations

PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab

Minaxi Jhawer et al. Cancer Res. .

"VSports最新版本" Erratum in

  • Cancer Res. 2008 Aug 15;68(16):6859. Soler, Roman Perez [corrected to Perez-Soler, Roman]
  • Cancer Res. 2009 Dec 1;69(23):9156

V体育平台登录 - Abstract

Cetuximab is a monoclonal antibody that targets the human epidermal growth factor receptor (EGFR). Although approved for use in EGFR-overexpressing advanced colorectal cancer, recent studies have shown a lack of association between EGFR overexpression and cetuximab response, requiring the identification of novel biomarkers predictive of response to this agent. To do so, 22 colon cancer cell lines were screened for cetuximab response in vitro and sensitive and resistant lines were identified. In sensitive cell lines, cetuximab induced a G(0)-G(1) arrest without inducing apoptosis VSports手机版. Notably, cetuximab-sensitive but not cetuximab-resistant cell lines were preferentially responsive to EGF-stimulated growth. Whereas neither EGFR protein/mRNA expression nor gene copy number correlated with cetuximab response, examination of the mutation status of signaling components downstream of EGFR showed that cell lines with activating PIK3CA mutations or loss of PTEN expression (PTEN null) were more resistant to cetuximab than PIK3CA wild type (WT)/PTEN-expressing cell lines (14 +/- 5. 0% versus 38. 5 +/- 6. 4% growth inhibition, mean +/- SE; P = 0. 008). Consistently, PIK3CA mutant isogenic HCT116 cells showed increased resistance to cetuximab compared with PIK3CA WT controls. Furthermore, cell lines that were PIK3CA mutant/PTEN null and Ras/BRAF mutant were highly resistant to cetuximab compared with those without dual mutations/PTEN loss (10. 8 +/- 4. 3% versus 38. 8 +/- 5. 9% growth inhibition, respectively; P = 0. 002), indicating that constitutive and simultaneous activation of the Ras and PIK3CA pathways confers maximal resistance to this agent. A priori screening of colon tumors for PTEN expression status and PIK3CA and Ras/BRAF mutation status could help stratify patients likely to benefit from this therapy. .

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Figures

Figure 1
Figure 1
(A) Differential sensitivity of colon cancer cell lines to 72 h cetuximab treatment. Shown for simplicity are the 3 most sensitive and resistant cell lines of the 22 cell lines screened for cetuximab response. Values shown are the mean ± SEM of n=3–5 experiments. (B) Differential sensitivity of colon cancer cells to cetuximab in vivo. 5×106 cells of the cetuximab sensitive (GEO) and resistant (LIM2405) colon cancer cell lines were injected in SCID mice. Once palpable tumors had formed animals were injected with cetuximab (10 mg/kg) or PBS (control), biweekly, for 2 weeks following which animals were sacrificed, tumors excised and tumor volume calculated as in Materials and Methods.
Figure 2
Figure 2
Summary of cell cycle analysis of cetuximab sensitive (GEO, LIM1215, SW403) and resistant (LIM2405, HCT116, HCT15) colon cancer cell lines. For assessment of cell cycle distribution, cells were treated for 24 hours with 20 µg/ml cetuximab (A–C). For assessment of apoptosis, cells were treated with 20 µg/ml cetuximab or 5 µM 5FU for 72h (D). Cell cycle distribution and apoptosis was assessed by PI staining and FACS analysis. Values shown are mean ± SEM, n=3, #P<0.05.
Figure 3
Figure 3
Basal EGFR mRNA, protein expression, or EGFR copy number does not correlate with cetuximab response. (A) Correlation of basal EGFR mRNA expression as assessed in exponentially growing colon cancer cells by Q-RT-PCR and cetuximab response at the 20 µg/ml dose. (B) EGFR protein expression in the 22 cell lines as assessed by western blot analysis. (C) EGFR (red) copy number as determined by FISH analysis in the 3 sensitive and 3 resistant cell lines. CEP7 (green) was used as marker of chromosome 7.
Figure 4
Figure 4
EGF selectively stimulates cell growth in cetuximab sensitive cell lines. (A) Effect of EGF treatment on cell cycle progression. Cells were treated for 24 hours with 0.5 ng/ml EGF and cell cycle distribution determined by PI staining and FACS analysis. Values shown are mean ± SEM from a representative experiment, # p<0.05. Experiments were repeated 3 separate times. (B) The 3-most cetuximab sensitive and resistant cell lines were treated for 24–72 hours with 0.5 ng/ml EGF, EGF + cetuximab (20 µg/ml) or left untreated (control). Cell growth was assayed by MTT assay. Values shown are mean ± SEM from a representative experiment, # p<0.05. Experiments were repeated 3 separate times.
Figure 5
Figure 5
Mutation status and response to cetuximab in vitro. (A) Cetuximab response in the 22 colon cancer cell line panel separated according to PIK3CA mutation/PTEN expression status (*p=0.008), Ras/BRAF mutation status (p=0.11), or according to presence or absence of synchronous mutations in the PIK3CA/PTEN and the K-Ras/BRAF pathways (*p=0.002). (B) Cetuximab response in isogenic PIK3CA mutant and WT HCT116 cell lines. Cells were serum starved overnight then treated with 20 or 100 µg/ml cetuximab for 24h in medium containing 0.5% serum. Differential sensitivity was assessed by direct counting of cell number. (C) Cetuximab response in isogenic Ras mutant and WT HCT116 cells. Cetuximab response was determined 24h post treatment by counting cell number.
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