Although epidermal growth factor receptor (EGFR) has been identified as a potent “oncogenic driver” in various tumors of epithelial origin, EGFR-targeted therapies are often of limited success. One of the challenges of improving targeted therapies is to overcome bypassing signaling pathways.

Analysis of RNA-seq data of 1006 cell lines from the Cancer Cell Line Encyclopedia (CCLE) revealed that more than 12% of carcinoma cell lines expressed markedly elevated mRNA levels of colony-stimulating factor (CSF)-1 receptor (CSF-1R). Since epithelial cells also express CSF-1, elevated levels of CSF-1R may participate in providing alternative growth and survival signals under targeted therapies. To address this question, we ectopically expressed CSF-1R in A431 cells that express EGFR at high levels, but no biologically relevant level of CSF-1R. In the presence of EGFR inhibitor gefitinib, CSF-1R provided a significant growth advantage in A431 cells. As expected, activation of both receptors, EGFR or CSF-1R, induced phosphorylation of extracellular signal-regulated kinase (Erk)1/2, Akt, protein kinase C (PKC) and signal transducer and activator of transcription (STAT)3. However, EGFR, but not CSF-1R, also induced STAT5 phosphorylation. Inhibitor of phosphatidylinositol 3–kinase (PI3K) (AZD8186), MAPK/ERK kinase (MEK)1/2 (U0126), PKCs (Bisindolylmaleimide I or Gö6976) or STAT3 (Stattic) partially reduced proliferation of CSF-1R expressing A431 cells in the presence of gefitinib. Moreover, multi-kinase inhibitor, cabozantinib, suppressed CSF-1R activation and drastically reduced cell growth when combined with gefitinib. These data suggest that CSF-1R has the potential to reduce sensitivity to gefitinib and may be involved in resistance development.

尽管表皮生长因子受体（EGFR）在各种上皮起源的肿瘤中已被确定为有效的“致癌驱动因子”，但以EGFR为靶点的疗法往往取得了有限的成功。改善靶向疗法的挑战之一是克服旁路信号通路。

分析来自癌细胞系百科全书（CCLE）的1006个细胞系的RNA-seq数据后发现，超过12％的癌细胞系表达了集落刺激因子（CSF）-1受体（CSF-1R）的mRNA水平显着升高。由于上皮细胞也表达CSF-1，因此在靶向治疗下，升高的CSF-1R水平可能参与提供替代的生长和生存信号。为了解决这个问题，我们在高水平表达EGFR的A431细胞中异位表达CSF-1R，但没有生物学相关水平的CSF-1R。在EGFR抑制剂吉非替尼存在的情况下，CSF-1R在A431细胞中提供了显着的生长优势。如预期的那样，两种受体EGFR或CSF-1R的激活都诱导了细胞外信号调节激酶（Erk）1/2，Akt，蛋白激酶C（PKC）以及信号转导和转录激活剂（STAT）3。然而，EGFR而不是CSF-1R也诱导STAT5磷酸化。磷脂酰肌醇3激酶（PI3K）（AZD8186），MAPK / ERK激酶（MEK）1/2（U0126），PKCs（双吲哚基马来酰亚胺I或Gö6976）或STAT3（静态）的抑制剂可部分降低CSF-1R表达A431细胞在S431中的增殖吉非替尼的存在。此外，与吉非替尼联合使用时，多激酶抑制剂卡波替尼可抑制CSF-1R活化并显着降低细胞生长。这些数据表明，CSF-1R有可能降低对吉非替尼的敏感性，并可能参与耐药性的发展。在吉非替尼存在的情况下，PKC（Bisindolylmaleimide I或Gö6976）或STAT3（Stattic）会部分降低表达CSF-1R的A431细胞的增殖。此外，与吉非替尼联合使用时，多激酶抑制剂卡波替尼可抑制CSF-1R活化并显着降低细胞生长。这些数据表明，CSF-1R有可能降低对吉非替尼的敏感性，并可能参与耐药性的发展。在吉非替尼存在的情况下，PKC（Bisindolylmaleimide I或Gö6976）或STAT3（Stattic）会部分降低表达CSF-1R的A431细胞的增殖。此外，与吉非替尼联合使用时，多激酶抑制剂卡波替尼可抑制CSF-1R活化并显着降低细胞生长。这些数据表明，CSF-1R有可能降低对吉非替尼的敏感性，并可能参与耐药性的发展。