Enhanced efficacy of AKT and FAK kinase combined inhibition in squamous cell lung carcinomas with stable reduction in PTEN

Abstract

Squamous cell lung carcinoma (SCC) accounts for 30% of patients with NSCLC and to date, no molecular targeted agents are approved for this type of tumor. However, recent studies have revealed several oncogenic mutations in SCC patients, including an alteration of the PI3K/AKT pathway, i.e. PI3K point mutations and amplification, AKT mutations and loss or reduced PTEN expression. Prompted by our observation of a correlation between PTEN loss and FAK phosphorylation in a cohort of patients with stage IV SCC, we evaluated the relevance of PTEN loss in cancer progression as well as the efficacy of a new combined treatment with the pan PI3K inhibitor buparlisip and the FAK inhibitor defactinib. An increase in AKT and FAK phosphorylation, associated with increased proliferation and invasiveness, paralleled by the acquisition of mesenchymal markers, and overexpression of the oncomir miR-21 were observed in SKMES-1-derived cell clones with a stable reduction of PTEN. Notably, the combined treatment induced a synergistic inhibition of cell proliferation, and a significant reduction in cell migration and invasion only in cells with reduced PTEN. The molecular mechanisms underlying these findings were unraveled using a specific RTK array that showed a reduction in phosphorylation of key kinases such as JNK, GSK-3 α/β, and AMPK-α2, due to the concomitant decrease in AKT and FAK activation. In conclusion, the combination of buparlisib and defactinib was effective against cells with reduced PTEN and warrants further studies as a novel therapeutic strategy for stage IV SCC patients with loss of PTEN expression.

EYA2 promotes lung cancer cell proliferation by downregulating the expression of PTEN

“…PTEN acts as a critical tumor suppressor by inhibiting PI3K pathway [ 27 ]. The inactivation of PTEN by genetic (Loss of heterozygosity, mutations) or epigenetic regulation (promoter hypermethylation, miRNAs) has been found in various tumors [ 29 , 53 – 55 ]. In the present study, we showed that EYA2 could suppress the PTEN expression via modulation of miR-93, which negatively regulated the expression of PTEN by binding to its 3′-UTR directly.…”

RAC1 Takes the Lead in Solid Tumors

“…Epithelial–mesenchymal transition (EMT) is one of the cardinal features associated with the metastatic process in tumor cells wherein these cells lose their polarity, shape (especially in the case of epithelial tumors; from epithelioid to mesenchymal), and cell-to-cell adhesion in order to acquire migratory and invasive potential as well as stem-like features [80]. Understandably, RAC1 plays an important role in EMT by virtue of its property to regulate cell polarity, migration, invasion, and stemness [81] in different cancers including gastric adenocarcinoma [82], squamous lung cancer [83,84], and colorectal cancers [85]. A mechanism involving RAC1 has been reported to involve the PI3K/AKT-RAC1-JNK axis in gastric adenocarcinoma [82], PI3K in squamous lung cancer [83,84], and the activation of STAT3 in colorectal cancer [85], highlighting the direct association of RAC1 activation and tumor aggressiveness.…”

New Treatment Opportunities in Phosphatase and Tensin Homolog (PTEN)-Deficient Tumors: Focus on PTEN/Focal Adhesion Kinase Pathway

“…Currently, this strategy ( 74 ) provides a better treatment for PTEN-null T-ALL cells compared to the inhibition of PI3K/AKT alone. The same approach has been tested by our group in a preclinical model on SCC with stable PTEN abrogation, demonstrating that a simultaneous inhibition of both targets induces synergistic reduction of cell growth and invasiveness ( 75 ).…”

“…In our recent article ( 75 ), we analyzed the correlation between PTEN loss and FAK activation in squamous NSCLC patients. As previously reported ( 76 ), PTEN levels are reduced in 70 and 77% of patients with lung squamous (SCC) or AD histology, respectively.…”