Targeting the Phosphoinositide 3-Kinase p110-α Isoform Impairs Cell Proliferation, Survival, and Tumor Growth in Small Cell Lung Cancer

Wojtalla, Anna; Fischer, Barbara; Kotelevets, Nataliya; Mauri, Francesco; Sobek, Jens; Rehrauer, Hubert; Wotzkow, Carlos; Tschan, Mario P.; Seckl, Michael J.; Zangemeister‐Wittke, Uwe; Arcaro, Alexandre

doi:10.1158/1078-0432.ccr-12-1138

Cited by 28 publications

(25 citation statements)

References 28 publications

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“…These results strongly suggest that PF-4989216 is an effective PI3K inhibitor able to induce in vitro and in vivo antitumor activity in SCLC with PIK3CA mutation. These results are also in line with a recent report that targeting the p110a isoform impaired tumor progression in SCLCs (31).…”

Section: Discussionsupporting

confidence: 92%

Targeting Small Cell Lung Cancer Harboring PIK3CA Mutation with a Selective Oral PI3K Inhibitor PF-4989216

Walls

Baxi

Mehta

et al. 2014

Clinical Cancer Research

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Purpose: Constitutive activation of phosphoinositide 3-kinase (PI3K) occurs frequently in many human tumors via either gene mutation in the p110a catalytic subunit of PI3K or functional loss of tumor suppressor PTEN. Patients with small-cell lung cancer (SCLC) have very poor prognosis and survival rates such that an effective targeted therapy is in strong demand for these patients. In this study, we characterized the highly selective oral PI3K inhibitor, PF-4989216, in preclinical SCLC models to investigate whether targeting the PI3K pathway is an effective targeted therapy option for SCLCs that harbor a PIK3CA mutation.Experimental Design: A panel of SCLC cell lines with PIK3CA mutation or PTEN loss were treated with PF-4989216 in several in vitro assays, including PI3K pathway signaling, cell viability, apoptosis, cell-cycle progression, and cell transformation. SCLC cell lines that were sensitive in vitro to PF-4989216 were further evaluated by in vivo animal studies to determine the pharmacokinetic/pharmacodynamic relationship and tumor growth inhibition (TGI) by PF-4989216 treatment.Results: PF-4989216 inhibited PI3K downstream signaling and subsequently led to apoptosis induction, and inhibition in cell viability, transformation, and xenograft tumor growth in SCLCs harboring PIK3CA mutation. In SCLCs with PTEN loss, PF-4989216 also inhibited PI3K signaling but did not induce BCL2-interacting mediator (BIM)-mediated apoptosis nor was there any effect on cell viability or transformation. These results implicate differential tumorigenesis and apoptosis mechanisms in SCLCs harboring PIK3CA mutation versus PTEN loss.Conclusions: Our results suggest that PF-4989216 is a potential cancer drug candidate for patients with SCLC with PIK3CA mutation but not PTEN loss. Clin Cancer Res; 20(3); 631-43. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 92%

Targeting Small Cell Lung Cancer Harboring PIK3CA Mutation with a Selective Oral PI3K Inhibitor PF-4989216

Walls

Baxi

Mehta

et al. 2014

Clinical Cancer Research

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“…This pathway may play a critical role in LCNEC tumorigenesis. Genetic alterations in this pathway have been noted as a promising therapeutic target in SCLC (12,(19)(20)(21)(22)(23), and targeted therapy for this pathway may also be promising in LCNEC. Mutual exclusiveness was observed in the copy number gain of each MYC family gene.…”

Section: Discussionmentioning

confidence: 99%

Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung

Miyoshi

Umemura

Matsumura

et al. 2017

Clinical Cancer Research

149

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Purpose: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations.Experimental Design: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non-small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases).Results: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P ¼ 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%-100%).Conclusions: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/ mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies.

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“…Importantly, all of these alterations occurred in a mutually exclusive fashion Ross et al 2014;Umemura et al 2014). Activation of this pathway was shown to facilitate aberrant regulation of proliferation, survival, and migration, giving the tumor cell a selective advantage (Wojtalla et al 2013).…”

Section: Genetic Landscape In Sclcmentioning

confidence: 99%

Origins, genetic landscape, and emerging therapies of small cell lung cancer

2015

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Lung cancer is the leading cause of cancer deaths, with small cell lung cancer (SCLC) representing the most aggressive subtype. Standard treatments have not changed in decades, and the 5-year survival rate has remained <7%. Genomic analyses have identified key driver mutations of SCLC that were subsequently validated in animal models of SCLC. To provide better treatment options, a deeper understanding of the cellular and molecular mechanisms underlying SCLC initiation, progression, metastasis, and acquisition of resistance is required. In this review, we describe the genetic landscape of SCLC, features of the cell of origin, and targeted therapeutic approaches.

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Targeting the Phosphoinositide 3-Kinase p110-α Isoform Impairs Cell Proliferation, Survival, and Tumor Growth in Small Cell Lung Cancer

Cited by 28 publications

References 28 publications

Targeting Small Cell Lung Cancer Harboring PIK3CA Mutation with a Selective Oral PI3K Inhibitor PF-4989216

Targeting Small Cell Lung Cancer Harboring PIK3CA Mutation with a Selective Oral PI3K Inhibitor PF-4989216

Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung

Origins, genetic landscape, and emerging therapies of small cell lung cancer

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