Targeted therapies for small cell lung cancer: Where do we stand?

Arcaro, Alexandre

doi:10.1016/j.critrevonc.2015.03.001

Cited by 46 publications

(22 citation statements)

References 134 publications

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“…In underdeveloped countries the percentage of SCLC cases may be higher. SCLC presents with a very large number of genetic alterations, including tumor suppressor genes, copy number gains and other somatic mutation in transcription factors, enzymes involved in chromatin modification, receptor tyrosine kinases and their downstream signaling components 1 . SCLC has a high propensity for early spread and a high initial responsiveness to cytotoxic chemotherapy usually followed by rapid development of resistance.…”

Section: Introductionmentioning

confidence: 99%

Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?

Bunn

Minna

Augustyn

et al. 2016

Journal of Thoracic Oncology

154

123

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Section: Introductionmentioning

confidence: 99%

Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?

Bunn

Minna

Augustyn

et al. 2016

Journal of Thoracic Oncology

154

123

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“…Small cell lung cancer (SCLC), a neuroendocrine carcinoma accounts for approximately 15% of all lung cancers. Although SCLC can be initially responsive to standard chemotherapy and radiation therapy, the recurrence rate is very high and there is a lack of effective second-line strategy [1]. Despite the improvements in diagnosis and therapeutic interventions made in the past two decades, the current prognosis for patients with SCLC remains poor.…”

Section: Introductionmentioning

confidence: 99%

Significantly mutated genes and regulatory pathways in SCLC—a meta-analysis

et al. 2017

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Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers and demands effective targeted therapeutic strategies. In this meta-analysis study, we aim to identify significantly mutated genes and regulatory pathways to help us better understand the progression of SCLC and to identify potential biomarkers. Besides ranking genes based on their mutation frequencies, we sought to identify statistically significant mutations in SCLC with the MutSigCV software. Our analysis identified several genes with relatively low mutation frequency, including PTEN, as highly significant (p<0.001), suggesting these genes may play an important role in the progression of SCLC. Our results also indicated mutations in genes involved in the axon guidance pathways likely play an important role in SCLC progression. In addition, we observed that the mutation rate was significantly higher in samples with RB1 gene mutated when compared to samples with wild type RB1, suggesting that RB1 status has significant impact on the mutation profile and disease progression in SCLC.

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“…Approximately 20% patients are classified as chemorefractory with disease progression within 90 days of completing chemotherapy (5,7). Multiple targeted therapies have been evaluated in SCLC, none improved patient outcomes (9), and SOC chemotherapy remains three decades after its introduction. A better understanding of SCLC biology, improved preclinical models, discovery of druggable targets, and biomarker-led clinical trials is warranted in this dismal disease.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Potter

Galvin

Brown

et al. 2016

Molecular Cancer Therapeutics

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Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell-derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient-derived model in vivo. These data add to a body of evidence that this combination should move toward the clinic.

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Targeted therapies for small cell lung cancer: Where do we stand?

Cited by 46 publications

References 134 publications

Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?

Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes?

Significantly mutated genes and regulatory pathways in SCLC—a meta-analysis

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

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