Inhibition of PI3K Pathway Reduces Invasiveness and Epithelial-to-Mesenchymal Transition in Squamous Lung Cancer Cell Lines Harboring <i>PIK3CA</i> Gene Alterations

Bonelli, Mara; Cavazzoni, Andrea; Saccani, Francesca; Alfieri, Roberta; Quaini, Federico; Monica, Silvia La; Galetti, Maricla; Cretella, Daniele; Caffarra, Cristina; Madeddu, Denise; Frati, Caterina; Lagrasta, Costanza Annamaria; Falco, Angela; Rossetti, Pietro; Fumarola, Claudia; Tiseo, Marcello; Petronini, Pier Giorgio; Ardizzoni, Andrea

doi:10.1158/1535-7163.mct-14-0892

Cited by 33 publications

(30 citation statements)

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“…Several lines of evidence indicate that the phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a key role in cancer stem cell biology (24), and some studies suggest that the PI3K/Akt pathway may regulated RhoA activity in various solid tumors (25, 26). We thus examined this signaling pathway in diffuse gastric cancer spheroid cells.…”

Section: Resultsmentioning

confidence: 99%

Chemotherapy Resistance in Diffuse-Type Gastric Adenocarcinoma Is Mediated by RhoA Activation in Cancer Stem-Like Cells

Yoon

Cho

Aksoy

et al. 2016

Clinical Cancer Research

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Purpose The Lauren diffuse type of gastric adenocarcinoma (DGA), as opposed to the intestinal type (IGA), often harbor mutations in RHOA but little is known about the role of RhoA in DGA. Experimental Design We examined RhoA activity and RhoA pathway inhibition in DGA cell lines and in two mouse xenograft models. RhoA activity was also assessed in patient tumor samples. Results RhoA activity was higher in DGA compared to IGA cell lines, and was further increased when grown as spheroids to enrich for cancer stem-like cells (CSC) or when sorted using the gastric CSC marker CD44. RhoA shRNA or the RhoA inhibitor Rhosin decreased expression of the stem cell transcription factor, Sox2, and decreased spheroid formation by 78–81%. DGA spheroid cells had 3–5 fold greater migration and invasion than monolayer cells, and this activity was Rho-dependent. Diffuse GA spheroid cells were resistant in a cytotoxicity assay to 5-fluorouracil and cisplatin chemotherapy, and this resistance could be reversed with RhoA pathway inhibition. In two xenograft models, cisplatin inhibited tumor growth by 40–50%, RhoA inhibition by 32–60%, and the combination by 77–83%. In 288 patient tumors, increased RhoA activity correlated with worse OS in DGA patients (p=0.017) but not in IGA patients (p=0.612). Conclusions RhoA signaling promotes CSC phenotypes in DGA cells. Increased RhoA activity is correlated with worse OS in DGA patients and RhoA inhibition can reverse chemotherapy resistance in DGA CSC and in tumor xenografts. Thus the RhoA pathway is a promising new target in DGA patients.

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Section: Resultsmentioning

confidence: 99%

Chemotherapy Resistance in Diffuse-Type Gastric Adenocarcinoma Is Mediated by RhoA Activation in Cancer Stem-Like Cells

Yoon

Cho

Aksoy

et al. 2016

Clinical Cancer Research

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“…A previous study reported that co-treatment of an MEK inhibitor and BKM120 in NSCLC cell lines with KRAS mutations significantly inhibited the growth of tumors both in vitro and in vivo (24). In the clinic, drug decisions are usually based on a genetic mutation test to govern the use of drugs common in personalized therapy (25).…”

Section: Discussionmentioning

confidence: 99%

Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations

et al. 2016

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EGFR and KRAS mutations are the two most common driver mutations in non-small cell lung cancer (NSCLC). Molecular target-based therapy using small molecules such as gefitinib has been used for inhibiting EGFR with good initial responses; however, drug resistance is common when using a mono-targeting strategy. At present, KRAS remains an undruggable target. As such, the development of new drugs targeting the downstream of KRAS and EGFR and their crosstalk pathways is critically needed to effectively treat NSCLC. The present study aimed to elucidate the anticancer effects of PI3K (BKM120) and MEK (PD1056309) inhibitors on NSCLC cell lines with KRAS or EGFR mutations. Inhibition of the EGFR and KRAS downstream P13K pathway using BKM120 significantly inhibited the growth of NSCLC cell lines with either EGFR or KRAS mutations. In addition, significant cell cycle arrest and induction of apoptosis were observed following BKM120 treatment. Notably, although the A549 and H358 NSCLC cell lines harbor the same KRAS mutation, A549 cells were less sensitive than H358 cells in the response to BKM120 treatment. Similarly, PC-9 and H1650 cells harbor the same EGFR mutation, however, H1650 was less sensitive to BKM120. Different sensitivity between NSCLC cell lines with the same oncogenic mutation suggests that multiple crosstalk pathways exit. Combined usage of BKM120 and PD1056309 synergistically enhanced apoptosis in the A549 cells and mildly enhanced apoptosis in the H1650 and H358 cells, suggesting the crosstalk of the MEK pathway with the P13K/Akt pathways in these cell lines. Overall, our findings suggest that inhibition of EGFR and KRAS downstream with a P13K/Akt inhibitor could be useful for treating NSCLC. However, for NSCLC exhibiting crosstalk with other survival pathways, such as the MEK pathway, combination treatment is required.

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“…Briefly, 200 cells were seeded and after 1–3 days the spheroids were formed and treated with drugs or vehicle for 96 hours. The effects of the drugs were evaluated in terms of volume changes as previously described [16].…”

Section: Methodsmentioning

confidence: 99%

Combined Inhibition of CDK4/6 and PI3K/AKT/mTOR Pathways Induces a Synergistic Anti-Tumor Effect in Malignant Pleural Mesothelioma Cells

et al. 2017

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Malignant pleural mesothelioma (MPM) is a progressive malignancy associated to the exposure of asbestos fibers. The most frequently inactivated tumor suppressor gene in MPM is CDKN2A/ARF, encoding for the cell cycle inhibitors p16INK4a and p14ARF, deleted in about 70% of MPM cases. Considering the high frequency of alterations of this gene, we tested in MPM cells the efficacy of palbociclib (PD-0332991), a highly selective inhibitor of cyclin-dependent kinase (CDK) 4/6. The analyses were performed on a panel of MPM cell lines and on two primary culture cells from pleural effusion of patients with MPM. All the MPM cell lines, as well as the primary cultures, were sensitive to palbociclib with a significant blockade in G0/G1 phase of the cell cycle and with the acquisition of a senescent phenotype. Palbociclib reduced the phosphorylation levels of CDK6 and Rb, the expression of myc with a concomitant increased phosphorylation of AKT. Based on these results, we tested the efficacy of the combination of palbociclib with the PI3K inhibitors NVP-BEZ235 or NVP-BYL719. After palbociclib treatment, the sequential association with PI3K inhibitors synergistically hampered cell proliferation and strongly increased the percentage of senescent cells. In addition, AKT activation was repressed while p53 and p21 were up-regulated. Interestingly, two cycles of sequential drug administration produced irreversible growth arrest and senescent phenotype that were maintained even after drug withdrawal. These findings suggest that the sequential association of palbociclib with PI3K inhibitors may represent a valuable therapeutic option for the treatment of MPM.

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Inhibition of PI3K Pathway Reduces Invasiveness and Epithelial-to-Mesenchymal Transition in Squamous Lung Cancer Cell Lines Harboring PIK3CA Gene Alterations

Cited by 33 publications

References 50 publications

Chemotherapy Resistance in Diffuse-Type Gastric Adenocarcinoma Is Mediated by RhoA Activation in Cancer Stem-Like Cells

Chemotherapy Resistance in Diffuse-Type Gastric Adenocarcinoma Is Mediated by RhoA Activation in Cancer Stem-Like Cells

Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations

Combined Inhibition of CDK4/6 and PI3K/AKT/mTOR Pathways Induces a Synergistic Anti-Tumor Effect in Malignant Pleural Mesothelioma Cells

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