Depleting receptor tyrosine kinases EGFR and HER2 overcomes resistance to EGFR inhibitors in colorectal cancer.
Depleting receptor tyrosine kinases EGFR and HER2 overcomes resistance to EGFR inhibitors in colorectal cancer.
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DOI：
10.1186/s13046-022-02389-z
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发表时间：
2022-06-02
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--
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表皮生长因子受体(EGFR)抑制剂，包括西妥昔单抗和帕尼单抗，是治疗结直肠癌(CRC)的有价值的药物，但对这些抑制剂的耐药性很常见。这种耐药性的原因尚不清楚，这阻碍了更好的治疗策略的发展。尽管KRAS、BRAF和PIK3CA的激活突变被认为是结直肠癌对EGFR抑制剂耐药的主要驱动因素，但针对这些耐药驱动因素的治疗并未产生实质性的临床益处。我们利用细胞系和小鼠肿瘤模型(细胞系异种移植和患者来源的异种移植)，进行了EGFR和/或其家族成员HER2的遗传和药物耗竭实验，包括EGFR突变体、抑制EGFR配体脱落和信号蛋白的生化分析，以揭示结直肠癌对EGFR抑制剂的耐药机制，并评估PEPDG278D的治疗活性。PEPDG278D是一种能诱导EGFR和HER2降解的重组人蛋白。大肠癌细胞对西妥昔单抗和帕尼单抗的敏感性与这些药物诱导EGFR下调的能力有关。无论KRAS、BRAF和PIK3CA突变如何，PEPDG278D都能通过导致EGFR和HER2的大量缺失来强烈抑制大肠癌细胞的致癌信号和生长。抑制EGFR或HER2的siRNA也能抑制耐受EGFR抑制剂的CRC细胞。携带突变的KRAS、BRAF和/或PIK3CA的肿瘤也过度表达EGFR配体，进一步表明EGFR信号对肿瘤仍然重要。虽然过量的肿瘤产生的高亲和力EGFR配体阻止了PEPDG278D的靶向结合，但ADAM10和ADAM17的抑制剂aderbasib通过抑制配体的脱落使PEPDG278D能够发挥强大的抗肿瘤活性。此外，在PEPDG278D和阿德巴西布的组合中加入治疗结直肠癌常用的氟尿嘧啶，进一步增强了对肿瘤的抑制作用。我们的研究表明，结直肠癌对EGFR抑制剂的耐药性主要是由于抑制剂无法下调其靶点，基于PEPDG278D的联合治疗克服了耐药性。网上版载有补充材料，可在10.1186/s13046-022-02389-z查阅。
Epidermal growth factor receptor (EGFR) inhibitors, including cetuximab and panitumumab, are valuable therapeutics for colorectal cancer (CRC), but resistance to these inhibitors is common. The reason for such resistance is not well understood, which hampers development of better therapeutic strategies. Although activating mutations in KRAS, BRAF and PIK3CA are considered major drivers of CRC resistance to EGFR inhibitors, therapeutic targeting of these drug resistance drivers has not produced substantial clinical benefit. We exploited cell lines and mouse tumor models (cell line xenografts and patient derived xenografts) for experiments of genetic and pharmacologic depletion of EGFR and/or its family member HER2, including EGFR mutants, inhibition of EGFR ligand shedding, and biochemical analysis of signaling proteins, to delineate the mechanism of CRC resistance to EGFR inhibitors and to assess the therapeutic activity of PEPDG278D, which is a recombinant human protein that induces the degradation of both EGFR and HER2. The sensitivity of CRC cells to cetuximab and panitumumab correlates with the ability of these drugs to induce EGFR downregulation. PEPDG278D strongly inhibits oncogenic signaling and growth of CRC cells by causing profound depletion of EGFR and HER2, regardless of activating mutations of KRAS, BRAF and PIK3CA. siRNA knockdown of EGFR or HER2 also inhibits CRC cells resistant to EGFR inhibitors. Tumors harboring mutated KRAS, BRAF and/or PIK3CA also overexpress EGFR ligands, further suggesting that EGFR signaling remains important to the tumors. While excessive tumor-generated high-affinity EGFR ligands block target engagement by PEPDG278D, aderbasib, an inhibitor of ADAM10 and ADAM17, enables PEPDG278D to exert strong antitumor activity by inhibiting ligand shedding. Moreover, adding fluorouracil, which is commonly used in CRC treatment, to the combination of PEPDG278D and aderbasib further enhances tumor inhibition. Our study shows that CRC resistance to EGFR inhibitors results primarily from the inability of the inhibitors to downregulate their target and that a PEPDG278D-based combination treatment overcomes the resistance. The online version contains supplementary material available at 10.1186/s13046-022-02389-z.
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影响因子：
3.6
作者：
Price T;Ang A;Boedigheimer M;Kim TW;Li J;Cascinu S;Ruff P;Satya Suresh A;Thomas A;Tjulandin S;Peeters M
通讯作者：
Peeters M
影响因子：
64.5
作者：
Garrett, TPJ;McKern, NM;Ward, CW
通讯作者：
Ward, CW
影响因子：
7.4
作者：
Kennedy, Sean P.;Han, Jeremy Z. R.;Croucher, David R.
通讯作者：
Croucher, David R.
影响因子：
64.5
作者：
Ogiso, H;Ishitani, R;Yokoyama, S
通讯作者：
Yokoyama, S
DOI：
10.1200/jco.2017.72.7107
发表时间：
2018-05-01
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Juric D;Rodon J;Tabernero J;Janku F;Burris HA;Schellens JHM;Middleton MR;Berlin J;Schuler M;Gil-Martin M;Rugo HS;Seggewiss-Bernhardt R;Huang A;Bootle D;Demanse D;Blumenstein L;Coughlin C;Quadt C;Baselga J
通讯作者：
Baselga J