Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy

Bartucci, Monica; Svensson, Susanne; Romania, Paolo; Dattilo, Rosanna; Patrizii, Michele; Signore, Michele; Navarra, Simone; Lotti, Fiorenza; Biffoni, Mauro; Pilozzi, Emanuela; Duranti, Enrico; Martinelli, Simone; Rinaldo, Cinzia; Zeuner, Ann; Maugeri‐Saccà, Marcello; Eramo, Adriana; Maria, Ruggero De

doi:10.1038/cdd.2011.170

Cited by 160 publications

(115 citation statements)

References 35 publications

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“…15 Drug resistance has been previously demonstrated to be a feature of LCSC. 4,6,16 As expected, LCSCs used for this study were highly resistant to commonly used antineoplastic agents (Figure 1f), whereas their differentiated progeny and the commercial cell line H460 were overall more sensitive to drug-induced death. Altogether, these observations substantiate the validity of LCSC as cellular models in the search of new options for lung cancer therapy.…”

Section: Resultssupporting

confidence: 71%

Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer

et al. 2014

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Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-X L is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-X L inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-X L . In vivo, ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/ slow-proliferating LCSC strongly depend on Bcl-X L for their survival and indicate Bcl-X L inhibition as a potential therapeutic avenue in NSCLC. Cell Death and Differentiation (2014) 21, 1877-1888; doi:10.1038/cdd.2014.105; published online 18 July 2014Lung cancer is the leading cause of cancer-related death in men and is expected to become the main cause of cancer death for women in the near future. 1,2 There is increasing evidence that cancer stem cells (CSCs) have a key role in drug resistance, tumor progression and metastasis in multiple tumor types, including lung cancer. 3 Lung cancer stem cells (LCSCs) have been previously identified through different criteria including surface expression of CD133, c-kit or through functional properties such as selective drug survival, elevated aldehyde dehydrogenase (ALDH) activity, increased glycolysis and glycine/serine metabolism or low concentrations of reactive oxygen species and ATP. 4-9 Importantly, when inoculated into immunocompromised mice, LCSCs give rise to xenografts that histologically reproduce the tumor of origin, thus representing an improved model for in vivo testing of new targeted therapies. 10 Several tumors express elevated levels of anti-apoptotic Bcl-2 family proteins such as Bcl-2, Bcl-X L and Mcl-1, which affect the apoptotic threshold of neoplastic cells contributing to chemotherapy resistance. 11 Inhibition of anti-apoptotic Bcl-2 family members has been for long time regarded as a promising strategy to induce cancer cell death through approaches of increasing specificity. BH3 mimetics such as ABT-737, the related orally available ABT-263 (navitoclax) and the recently developed Bcl-2-selective inhibitor ABT-199 have been shown to exert an antitumor effect in preclinical and clinical settings either as single agents or in combination with conventional or targeted drugs. 12 Recently, a new role for Bcl-2 has emerged in acute myeloid leukemia (AML), whe...

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Section: Resultssupporting

confidence: 71%

Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer

et al. 2014

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“…34 In vivo studies Animal studies were performed according to the Istituto Superiore di Sanità guidelines on animal care under the Italian Ministry of Health authorization (D.M. n. 224/2011).…”

Section: Colony-forming Ability Assaymentioning

confidence: 99%

“…Paraffin sections (3 mm) were treated as previously described 34 and incubated with anti low and medium molecular weight cytokeratins (CKs, Dako, Fort Collins, CO, USA) and with the monoclonal antibody anti-TAZ (M2-616, BD Pharmingen, San Jose, CA, USA). For clinical data, formalin-fixed, paraffin-embedded sections were incubated with anti-ER (6F11, Leica, Milano, Italy), -PgR (1A6, Leica), -HER2 (A0485, Dako), -Ki-67 (MIB-1, Dako) and -TAZ.…”

Section: Immunohistochemistrymentioning

confidence: 99%

TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells

et al. 2014

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Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.

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“…Furthermore, a strong activation of Chk1 and cell cycle arrest were observed in patientderived non-small-cell lung cancer (NSCLC) stem cells compared to their corresponding differentiated cells after exposure to DNA damaging agents. Treatment with Chk1 inhibitors in combination with chemotherapy dramatically reduced the NSCLC stem cell population in vitro by promoting premature cell cycle progression and inducing mitotic catastrophe [43] . Although considerable reports suggest that competent DNA repair machinery is utilized by CSCs to survive DNA damaging agent treatment, some controversial observations also exist.…”

Section: Activation Of Cell Cycle Checkpoint Machinerymentioning

confidence: 99%

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

Wang

2015

WJBC

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The identification of cancer stem cells (CSCs) that are responsible for tumor initiation, growth, metastasis, and therapeutic resistance might lead to a new thinking on cancer treatments. Similar to stem cells, CSCs also display high resistance to radiotherapy and chemotherapy with genotoxic agents. Thus, conventional therapy may shrink the tumor volume but cannot eliminate cancer. Eradiation of CSCs represents a novel therapeutic strategy. CSCs possess a highly efficient DNA damage response (DDR) system, which is considered as a contributor to the resistance of these cells from exposures to DNA damaging agents. Targeting of enhanced DDR in CSCs is thus proposed to facilitate the eradication of CSCs by conventional therapeutics. To achieve this aim, a better understanding of the cellular responses to DNA damage in CSCs is needed. In addition to the protein kinases and enzymes that are involved in DDR, other processes that affect the DDR including chromatin remodeling should also be explored.

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Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy

Cited by 160 publications

References 35 publications

Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer

Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer

TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

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