Dual Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Blockade Is an Effective Radiosensitizing Strategy for the Treatment of Non–Small Cell Lung Cancer Harboring K-RAS Mutations

Abstract

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. NSCLC often harbors oncogenic K-RAS mutations that lead to the aberrant activation of several intracellular networks including the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. Oncogenic K-RAS predicts poor prognosis and resistance to treatment with ionizing radiation (IR). Oncogenic K-Ras expression in the respiratory epithelium is sufficient to initiate NSCLC tumorigenesis, which requires the catalytic subunit of PI3K. Thus, effective inhibition of the PI3K signaling should lead to significant antitumor effects. However, therapy with rapamycin analogues has yielded disappointing results due in part to compensatory up-regulation of AKT. We hypothesized that dual PI3K/mTOR blockade would overcome these limitations. We tested this hypothesis with BEZ235, a novel dual PI3K/mTOR inhibitor that has recently entered clinical development. We found that BEZ235 induces a striking antiproliferative effect both in transgenic mice with oncogenic K-RAS-induced NSCLC and in NSCLC cell lines expressing oncogenic K-RAS. We determined that treatment with BEZ235 was not sufficient to induce apoptosis. However, we found that dual PI3K/mTOR blockade effectively sensitizes NSCLC expressing oncogenic K-RAS to the proapoptotic effects of IR both in vitro and in vivo. We conclude that dual PI3K/mTOR blockade in combination with IR may benefit patients with NSCLC expressing oncogenic K-RAS. These findings may have general applicability in cancer therapy, because aberrant activation of PI3K occurs frequently in human cancer.

Molecular characterization of pulmonary sarcomatoid carcinoma: analysis of 33 cases

“…Although both TP53 and KRAS mutations are difficult targets for therapeutic intervention, there have been several clinical trials [29][30][31] for KRAS mutant adenocarcinomas, as well as preclinical model studies, 32 with the purpose of optimizing the treatment for this subgroup. Numerous studies have shown various therapeutic approaches for cancers harboring TP53 mutations, [33][34][35] including clinical trials specific for lung cancer employing therapies designed to inhibit immune blockade by the tumor (anti-CTLA 4 and anti-PD-1/PD-L1).…”

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

“…NVP-BEZ235 is a pan-PI3K inhibitor that acts against all of the isoforms of PI3K and PI3K mutants. Previous studies have demonstrated the efficacy of NVP-BEZ235 as an antitumor agent in vitro and in vivo in glioblastoma, multiple myeloma, melanoma, lymphoma, www.nature.com/aps Pal I et al Acta Pharmacologica Sinica npg sarcoma, breast, lung, and ovarian cancer models [84][85][86][87][88][89][90][91][92][93] . In the case of colon cancer, NVP-BEZ23 decreases cellular proliferation and causes sustained inhibition of mTORC1 and mTORC2 with a transient PI3K blockade with no subsequent effect on apoptosis either in vitro or in vivo in a GEM model.…”

Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma

“…The possible mechanisms by which this pathway regulates NPC proliferation include mutations in PI3K, PTEN deleted from chromosome 10 (PTEN), and Ras oncogene, as well as EGFR amplification (6)(7)(8). Previous studies showed that PI3K/Akt/mTOR signaling is frequently activated in many cancers, including lung, gastric, renal, and ovarian cancers (9)(10)(11)(12), and inhibition of this pathway could increase radiosensitivity (8,(13)(14)(15)(16)(17)(18). NPC cell lines and tissues also overexpressed phosphorylated Akt (p-Akt; refs.…”