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

Walls, Marlena; Baxi, Sangita M.; Mehta, Pramod P.; Liu, Kevin K.‐C.; Zhu, JinJiang; Estrella, Heather; Li, Chunze; Zientek, Michael; Zong, Qing; Smeal, Tod; Yin, Min-Jean

doi:10.1158/1078-0432.ccr-13-1663

Cited by 34 publications

(31 citation statements)

References 43 publications

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“…The growth of five bladder cancer cell lines could be inhibited by pictilisib to some extent, but only PIK3CA E545K mutant TCCSUP cells had an IC 50 as low as 1 μM. These observations are consistent with previous studies that suggested sensitivity to PI3K inhibitors was dependent on hotspot PIK3CA mutation status (9,10,29). We also revealed that AKT phosphorylation in TCCSUP cells could be inhibited by pictilisib to a nadir after 30 minutes, while remaining measurable in resistant J82 and T24 cells.…”

Section: Discussionsupporting

confidence: 90%

“…Therefore, inhibiting this signaling pathway may facilitate chemotherapy treatments (7,8). Preclinical studies and early clinical trials indicate that the treatment of several cancers including breast (9), lung (10), medulloblastoma (11), and pancreatic cancer (6) could benefit from PI3K inhibitors. It is plausible that such targeted therapeutic approaches against the PI3K/AKT pathway can be used in patients with advanced bladder cancer, either as a single agent or in combination, to decrease drug resistance and augment the efficacy of chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

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The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer

Zeng

Zhu

Hong

et al. 2017

Clinical Cancer Research

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Purpose Activation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs in over 40% of bladder urothelial cancers. The aim of this study is to determine the therapeutic potential, the underlying action and resistant mechanisms of drugs targeting the PI3K pathway. Experimental Design Urothelial cancer cell lines and patient-derived xenografts (PDXs) were analyzed for alterations of the PI3K pathway and for their sensitivity to the small molecule inhibitor pictilisib alone and in combination with cisplatin and/or gemcitabine. Potential predictive biomarkers for pictilisib were evaluated and RNA-sequencing was performed to explore drug resistance mechanisms. Results The bladder cancer cell line TCCSUP, which harbors a PIK3CA E545K mutation, was sensitive to pictilisib compared to cell lines with wild type PIK3CA. Pictilisib exhibited stronger anti-tumor activity in bladder cancer PDX models with PI3KCA H1047R mutation or amplification than control PDX model. Pictilisib synergized with cisplatin and/or gemcitabine in vitro, significantly delayed tumor growth and prolonged survival compared with single drug treatment in the PDX models. The phosphorylation of ribosomal protein S6 correlated with response to pictilisib both in vitro and in vivo, and could potentially serve as biomarker to predict response to pictilisib. Pictilisib activated the compensatory MEK/ERK pathways that likely contributed to pictilisib resistance, which was reversed by co-treatment with the RAF inhibitor sorafenib. RNA-sequencing of tumors resistant to treatment suggested that LSP1 down-regulation correlated with drug resistance. Conclusion These preclinical results provide new insights into the therapeutic potential of targeting the PI3K pathway for the treatment of bladder cancer.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer

Zeng

Zhu

Hong

et al. 2017

Clinical Cancer Research

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“…Instead, these cancers demonstrate a predictable pattern of loss of tumor suppressors RB and p53 in almost all cases, and loss of PTEN or PIK3CA mutations in up to 20% of cases (3, 4). In addition, we have previously demonstrated that BCL-2, the founding pro-survival BCL-2 family member, is highly expressed in 65% of cases (5, 6), as is BIM (7), a pro-apoptotic BCL-2 family member which sensitizes SCLC to targeted therapies, in particular BH3 mimetics (8).…”

Section: Introductionmentioning

confidence: 99%

Venetoclax Is Effective in Small-Cell Lung Cancers with High BCL-2 Expression

Lochmann

Floros

Naseri

et al. 2018

Clinical Cancer Research

103

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Purpose Small cell lung cancer (SCLC) is an often-fatal neuroendocrine carcinoma usually presenting as extensive disease, carrying a 3% five-year survival. Despite notable advances in SCLC genomics, new therapies remain elusive, largely due to a lack of druggable targets. Experimental Design We used a high-throughput drug screen to identify a venetoclax sensitive SCLC sub-population, and validated the findings with multiple patient-derived xenografts of SCLC. Results Our drug screen consisting of a very large collection of cell lines demonstrated that venetoclax, an FDA-approved BCL-2 inhibitor, was found to be active in a substantial fraction of SCLC cell lines. Venetoclax induced BIM-dependent apoptosis in vitro and blocked tumor growth and induced tumor regressions in mice bearing high BCL-2-expressing SCLC tumors in vivo. BCL-2 expression was a predictive biomarker for sensitivity in SCLC cell lines and was highly expressed in a subset of SCLC cell lines and tumors, suggesting that a substantial fraction of SCLC patients could benefit from venetoclax. Mechanistically, we uncover a novel role for gene methylation that helped discriminate high BCL-2-expressing SCLCs. Conclusions Altogether, our findings identify venetoclax as a promising new therapy for high BCL-2 expressing SCLCs.

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“…Except for TP53 , the percentage of tumors with either one of these driver mutations is less than 25%(2,3). Another recurrent event found in non-small cell lung cancers (NSCLC) and small cell lung cancers (SCLC) is activation of the PI3K/AKT pathway (3–5), which is frequently caused by loss of PTEN (6). Because of this confusing abundance of genetic mutations and other genetic anomalies, it is difficult to pinpoint specific drivers in any given patient and many lung cancer genetic drivers have yet to be identified (7).…”

Section: Introductionmentioning

confidence: 99%

Transposon Mutagenesis Screen Identifies Potential Lung Cancer Drivers and CUL3 as a Tumor Suppressor

Dorr

Janik

Weg

et al. 2015

Molecular Cancer Research

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Non-small cell lung cancers (NSCLCs) harbor thousands of passenger events that hide genetic drivers. Even highly recurrent events in NSCLC, such as mutations in PTEN, EGFR, KRAS, and ALK, are only detected in, at most, 30% of patients. Thus, many unidentified low-penetrant events are causing a significant portion of lung cancers. To detect low-penetrance drivers of NSCLC a forward genetic screen was performed in mice using the Sleeping Beauty (SB) DNA transposon as a random mutagen to generate lung tumors in a Pten deficient background. SB mutations coupled with Pten deficiency were sufficient to produce lung tumors in 29% of mice. Pten deficiency alone, without SB mutations, resulted in lung tumors in 11% of mice, while the rate in control mice was ~3%. In addition, thyroid cancer and other carcinomas as well as the presence of bronchiolar and alveolar epithelialization in mice deficient for Pten were also identified. Analysis of common transposon insertion sites identified 76 candidate cancer driver genes. These genes are frequently dysregulated in human lung cancers and implicate several signaling pathways. Cullin3 (Cul3), a member of an ubiquitin ligase complex that plays a role in the oxidative stress response pathway, was identified in the screen and evidence demonstrates that Cul3 functions as a tumor suppressor.

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

Cited by 34 publications

References 43 publications

The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer

The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer

Venetoclax Is Effective in Small-Cell Lung Cancers with High BCL-2 Expression

Transposon Mutagenesis Screen Identifies Potential Lung Cancer Drivers and CUL3 as a Tumor Suppressor

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