The PI3K/AKT pathway promotes gefitinib resistance in mutant KRAS lung adenocarcinoma by a deacetylase‐dependent mechanism

Abstract

To select the appropriate patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), it is important to gain a better understanding of the intracellular pathways leading to EGFR-TKI resistance, which is a common problem in patients with lung cancer. We recently reported that mutant KRAS adenocarcinoma is resistant to gefitinib as a result of amphiregulin and insulin-like growth factor-1 receptor overexpression. This resistance leads to inhibition of Ku70 acetylation, thus enhancing the BAX/Ku70 interaction and preventing apoptosis. Here, we determined the intracellular pathways involved in gefitinib resistance in lung cancers and explored the impact of their inhibition. We analyzed the activation of the phosphatidyl inositol-3-kinase (PI3K)/AKT pathway and the mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) pathway in lung tumors. The activation of AKT was associated with disease progression in tumors with wild-type EGFR from patients treated with gefitinib (phase II clinical trial IFCT0401). The administration of IGF1R-TKI or amphiregulin-directed shRNA decreased AKT signaling and restored gefitinib sensitivity in mutant KRAS cells. The combination of PI3K/AKT inhibition with gefitinib restored apoptosis via Ku70 downregulation and BAX release from Ku70. Deacetylase inhibitors, which decreased the BAX/Ku70 interaction, inhibited AKT signaling and induced gefitinib-dependent apoptosis. The PI3K/AKT pathway is thus a major pathway contributing to gefitinib resistance in lung tumors with KRAS mutation, through the regulation of the BAX/Ku70 interaction. This finding suggests that combined treatments could improve the outcomes for this subset of lung cancer patients, who have a poor prognosis.

EZH2 promotes tumor progression via regulating VEGF-A/AKT signaling in non-small cell lung cancer

“…The phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway has been documented in angiogenesis and lung cancer progression [12] and its activation stimulates VEGF-A expression [13]. However, whether EZH2 promotes tumor progression via VEGF-A/AKT signaling pathway warrants validation.…”

Enhanced Antitumor Activity of an Anti-5T4 Antibody–Drug Conjugate in Combination with PI3K/mTOR inhibitors or Taxanes

“…The PI3K/mTOR pathway plays an essential role in oncogenesis, and is implicated in the emergence of resistance to several therapeutic drugs in clinical settings, including erlotinib, gefitinib, or trastuzumab in patients with HER2-positive solid cancers (8)(9)(10)(11). Accordingly, agents that normalize PI3K/ mTOR pathway activity, including direct inhibitors of PI3K (GDC-0941), AKT (MK-2206), or mTOR (everolimus), have shown promising activity in trastuzumab-resistant patients when combined with trastuzumab both in preclinical and clinical investigations (12)(13)(14)(15).…”

New therapeutic perspectives in CCDC6 deficient lung cancer cells

“…As CCDC6 has been reported as a negative regulator of Amphiregulin transcription via CREB1, 47 a defect of CCDC6 protein in lung cancer might maintain an auto/paracrine activation of the EGFR signaling. 48 On this basis, many lung tumors that are EGFR negative might still be sensitive to the treatment with gefitinib. 49 Finally, as intratumor cell heterogeneity 50 still represents a great challenge in terms of tumor aggressiveness and therapy resistance, we propose that the identification of low CCDC6 expressing cells should identify the highly aggressive tumor variants that are likely to be sensitive to combinatorial strategies of therapy.…”