Department of Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
James Graham Brown Cancer Center, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
Cells. 2021 Jul 3;10(7):1679. doi: 10.3390/cells10071679.
Tyrosine kinase inhibitors (TKIs) targeting the kinase domain of the epidermal growth factor receptor (EGFR), such as erlotinib, have dramatically improved clinical outcomes of patients with EGFR-driven non-small cell lung carcinomas (NSCLCs). However, intrinsic or acquired resistance remains a clinical barrier to the success of FDA-approved EGFR TKIs. Multiple mechanisms of resistance have been identified, including the activation of prosurvival autophagy. We have previously shown that the expression and activity of PFKFB3-a known driver of glycolysis-is associated with resistance to erlotinib and that PFKFB3 inhibition improves the response of NSCLC cells to erlotinib. This study focuses on investigating the role of PFKFB3 in regulating erlotinib-driven autophagy to escape resistance to erlotinib. We evaluated the consequence of pharmacological inhibition of PFKFB3 on erlotinib-driven autophagy in NSCLC cells with different mutation statuses. Here, we identify PFKFB3 as a mediator of erlotinib-induced autophagy in NSCLCs. We demonstrate that PFKFB3 inhibition sensitizes NCSLCs to erlotinib via impairing autophagy flux. In summary, our studies uncovered a novel crosstalk between PFKFB3 and EGFR that regulates erlotinib-induced autophagy, thus contributing to erlotinib sensitivity in NSCLCs.
针对表皮生长因子受体 (EGFR) 激酶结构域的酪氨酸激酶抑制剂 (TKIs)，如厄洛替尼，显著改善了 EGFR 驱动的非小细胞肺癌 (NSCLC) 患者的临床结局。然而，内在或获得性耐药仍然是 FDA 批准的 EGFR TKI 成功的临床障碍。已经确定了多种耐药机制，包括促进生存的自噬的激活。我们之前已经表明，PFKFB3 的表达和活性 - 一种已知的糖酵解驱动因子 - 与厄洛替尼耐药有关，并且 PFKFB3 抑制可改善 NSCLC 细胞对厄洛替尼的反应。本研究重点研究 PFKFB3 在调节厄洛替尼驱动的自噬以逃避厄洛替尼耐药中的作用。我们评估了在具有不同突变状态的 NSCLC 细胞中，PFKFB3 的药理学抑制对厄洛替尼驱动的自噬的影响。在这里，我们确定 PFKFB3 是 NSCLCs 中厄洛替尼诱导的自噬的介质。我们证明 PFKFB3 抑制通过破坏自噬通量使 NCSLC 对厄洛替尼敏感。总之，我们的研究揭示了 PFKFB3 和 EGFR 之间的一种新的串扰，调节厄洛替尼诱导的自噬，从而有助于 NSCLCs 对厄洛替尼的敏感性。
