Background/objectives: Non-small cell lung cancer and pleural mesothelioma are among the most lethal and therapy-resistant tumors in humans. These tumors are diagnosed late, frequently present pleural effusion and develop drug resistance, and the treatment is often inefficient and largely alliative. Therefore, there is an urgent need to refine the selection of drugs and patients for personalized treatment. Methods: To progress the field, we performed a systematic literature review in line with the PRISMA guidelines followed by a narrative synthesis approach to identify themes. Results: The literature to date shows, in general, a positive correlation between the drug-sensitivity of patient-derived cells ex vivo and the clinical outcome. However, only a handful of these studies show a numerical correlation. This, along with the vast diversity of correlated techniques and parameters makes it difficult to directly compare the findings. To build a common knowledge base for future studies, we therefore offer a comprehensive summary of the literature, identify gaps, and suggest future avenues for research. Conclusions: We present unified recommendations for the collection, preparation, and ex vivo sensitivity testing of samples for the future development of personalized medicine.

Background: Tumors of the pleura, such as metastatic lung cancer and mesothelioma, are amongst the most lethal and therapy-resistant tumors. The first manifestation of the disease is often pleural effusion, the first available material for diagnosis. The five-year survival rate is exceptionally low, around 10–20%, and only a small proportion of patients harbor mutations that allow targeted treatments. Almost all patients develop resistance to treatment, which is often palliative. There is therefore an urgent need to refine the selection of drugs and patients for personalized treatment. Methods: We isolated and cultured cells from pleural effusions in 3D cell aggregates and compared their drug sensitivity ex vivo to the clinical response to the same chemotherapeutic agents, combined with targeted sequencing and network analysis. Results: The ex vivo drug response showed a positive correlation with the treatment response and survival of patients in the clinic, with a stronger link to overall survival than to progression-free survival. Cryopreserved cells showed a similar response to freshly collected cells from the clinic. Conclusions: The findings advance the field of ex vivo screening and present an opportunity to combine strategies for functional precision medicine with comprehensive characterization of disease for improved treatment and future management of lung cancer.

La famille des protéines p53 comprend p53, p63 et p73. Dans 50% des cas de cancers humains, le gène TP53 est altéré, tandis que les cancers avec un gène TP53 normal expriment souvent des isoformes oncogènes des protéines de la famille de p53. Cette thèse se concentre sur l'isoforme ΔNp73α, qui agit comme un inhibiteur dominant négatif de la signalisation p73/p53 dans divers cancers. Ce travail de thèse utilise des kératinocytes humains du prépuce transformés par les oncoprotéines E6 et E7 du papillomavirus humain 38 (38HK) du groupe β. Les 38HK surexpriment ΔNp73α par rapport aux kératinocytes primaires. Dans la première partie, il a été montré que ΔNp73α forme un complexe inhibiteur avec E2F4/p130, réprimant l'expression de gènes, y compris des suppresseurs de tumeur et des facteurs de sénescence. Dans la deuxième partie, l'interaction de ΔNp73α avec PARP14 a été caractérisée, indiquant que les protéines E6/E7 du β-HPV38 augmentent les niveaux de PARP14, qui agirait comme un répresseur de la signalisation p53 en maintenant les niveaux de p53 bas. Cela ouvre de nouvelles perspectives pour l'étude de la dérégulation de p53 par les HPV β et leur impact sur la carcinogenèse.