Growing clinical evidence for the interaction of the p53 genotype and response to induction chemotherapy in advanced non–small cell lung cancer

Kandioler, Daniela; Stamatis, Georgios; Eberhardt, Wilfried; Kappel, Sonja; Zöchbauer‐Müller, Sabine; Kührer, Irene; Mittlböck, Martina; Zwrtek, Ronald; Aigner, Clemens; Bichler, Christoph; Tichy, Victoria; Hudec, Marcus; Bachleitner, T.; End, Adelheid; Müller, Michael; Roth, Erich; Klepetko, Walter

doi:10.1016/j.jtcvs.2007.10.072

Cited by 44 publications

(31 citation statements)

References 25 publications

(30 reference statements)

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“…34,35 Interestingly, TP53 mutations have been found to be associated with resistance to cisplatin combined with etoposide 36 in nonsmall cell lung cancer as well as to cisplatin combined with ifosfamide. 37 The results from the former study 36 may be consistent with the observations regarding anthracyclines in as much as etoposide, being a Topo-II inhibitor, resembles the anthracyclines with respect to mechanism of action. Ifosfamide, on the contrary, is metabolized into cyclophosphamide in vivo.…”

Section: Tp53supporting

confidence: 82%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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Section: Tp53supporting

confidence: 82%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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“…Previous studies have investigated whether TP53 mutations are of prognostic value in predicting response to chemotherapy in NSCLC; the results are controversial (41). In a 35-patient study, the presence of mutant TP53 was highly indicative of resistance to cisplatin (P ¼ 0.002) (42), while in a study involving 253 patients, TP53-positive patients had a significantly greater survival benefit from adjuvant chemotherapy compared with TP53-negative patients (43). Another report in the International Adjuvant Lung Cancer Trial (IALT), a randomized trial of adjuvant cisplatin-based chemotherapy, found no correlation between TP53 mutation and outcome in 524 patients (44).…”

Section: Discussionmentioning

confidence: 99%

Ex Vivo Explant Cultures of Non–Small Cell Lung Carcinoma Enable Evaluation of Primary Tumor Responses to Anticancer Therapy

et al. 2017

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To improve treatment outcomes in non-small cell lung cancer (NSCLC), preclinical models that can better predict individual patient response to novel therapies are urgently needed. Using freshly resected tumor tissue, we describe an optimized ex vivo explant culture model that enables concurrent evaluation of NSCLC response to therapy while maintaining the tumor microenvironment. We found that approximately 70% of primary NSCLC specimens were amenable to explant culture with tissue integrity intact for up to 72 hours. Variations in cisplatin sensitivity were noted with approximately 50% of cases responding ex vivo. Notably, explant responses to cisplatin correlated significantly with patient survival (P ¼ 0.006) irrespective of tumor stage. In explant tissue, cisplatin-resistant tumors excluded platinum ions from tumor areas in contrast to cisplatin-sensitive tumors. Intact TP53 did not predict cisplatin sensitivity, but a positive correlation was observed between cisplatin sensitivity and TP53 mutation status (P ¼ 0.003). Treatment of NSCLC explants with the targeted agent TRAIL revealed differential sensitivity with the majority of tumors resistant to single-agent or cisplatin combination therapy. Overall, our results validated a rapid, reproducible, and low-cost platform for assessing drug responses in patient tumors ex vivo, thereby enabling preclinical testing of novel drugs and helping stratify patients using biomarker evaluation.

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“…To date, dysfunction of tumor suppressor genes has been confirmed as the most significant genetic damage in human cancers. Mutations or deletions of p53 occur in 50-70% of non-small cell lung cancers (NSCLCs) and are associated with poor prognosis of lung cancer patients (3,4).…”

Section: Introductionmentioning

confidence: 99%

Synergistic cytotoxic effects of recombinant human adenovirus p53 and radiation at various time points in A549 lung adenocarcinoma cells

Han

Zhao

et al. 2012

Oncology Letters

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Growing clinical evidence for the interaction of the p53 genotype and response to induction chemotherapy in advanced non–small cell lung cancer

Cited by 44 publications

References 25 publications

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Ex Vivo Explant Cultures of Non–Small Cell Lung Carcinoma Enable Evaluation of Primary Tumor Responses to Anticancer Therapy

Synergistic cytotoxic effects of recombinant human adenovirus p53 and radiation at various time points in A549 lung adenocarcinoma cells

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