Guo Lingchuan, Huang Shan, Wang Xinwei
Department of Pathology, Hospital of Suzhou University, Suzhou.
Department of Oncology, Tumor Hospital of Jiangsu Province, Nanjing, Jiangsu, China.
Onco Targets Ther. 2017 Nov 3;10:5281-5288. doi: 10.2147/OTT.S139382. eCollection 2017.
Osimertinib, an irreversible EGFR/HER2 inhibitor, has been found to be effective in the cancer cell with EGFR gene mutations in preclinical lung cancer models. However, the effect of osimertinib in colorectal cancer (CRC) cells is unclear. In the present study, we investigated how osimertinib suppresses CRC cells growth and potentiates effects of other chemotherapeutic drugs. We found that p73-mediated osimertinib-induced p53 upregulated modulator of apoptosis (PUMA) expression irrespective of p53 status following PI3K/AKT pathway inhibition in CRC cells. Furthermore, PUMA is required for osimertinib-induced apoptosis. In addition, osimertinib also synergized with 5-FU to induce significant apoptosis via PUMA in CRC cells. These results demonstrated a critical role of PUMA in mediating the anticancer effects of osimertinib and suggest that PUMA induction can be used as an indicator of osimertinib sensitivity.
奥希替尼是一种不可逆的表皮生长因子受体/人表皮生长因子受体2（EGFR/HER2）抑制剂，在临床前肺癌模型中，已发现其对具有EGFR基因突变的癌细胞有效。然而，奥希替尼在结直肠癌（CRC）细胞中的作用尚不清楚。在本研究中，我们研究了奥希替尼如何抑制CRC细胞生长并增强其他化疗药物的作用。我们发现，在CRC细胞中，PI3K/AKT途径抑制后，无论p53状态如何，p73介导的奥希替尼诱导的p53上调凋亡调节因子（PUMA）表达。此外，PUMA是奥希替尼诱导凋亡所必需的。此外，奥希替尼还与5-氟尿嘧啶协同作用，通过PUMA在CRC细胞中诱导显著凋亡。这些结果证明了PUMA在介导奥希替尼抗癌作用中的关键作用，并表明PUMA诱导可作为奥希替尼敏感性的指标。
