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Targeted therapies almost universally fail due to the development of resistance. EGFR-mutant non-small cell lung cancer (NSCLC) is a well characterized model of such mechanism. In this model, treatment with anti-EGFR therapy leads to resistance driven by the presence of the EGFR T790M mutation in about 50% of the cases. However, clinical data shows the EGFR resistance mutation is present only in a subpopulation of the relapsing cells. How cancer cells devoid of the EGFR T790M mutation become resistant is not known. The aim of this study is to explore if T790M-mediated resistance to anti-EGFR therapy can spread horizontally, through a mitosis-independent mechanism, among NSCLC cells. Immunodeficient mice (Rag2-/-Il2rg-/-) were engrafted with NSCLC HCC827 cells, harboring the Erlotinib-sensitive mutation EGFR E746-A750del, and H1975 cells, carrying the EGFR T790M Erlotinib-resistant mutation. These animals received a single inoculation of HCC827 cells in a single flank (n=10), or dual inoculation of HCC827 and H1975 cells in opposite flanks (n=20). Erlotinib was orally administered three times a week (25 mg/Kg) and tumors were collected at humane endpoint for genetic and transcriptomic analysis by next generation sequencing and digital PCR. T790M-driven resistance to Erlotinib was transferred in vivo from resistant to sensitive cells in dual inoculated animals, resulting in a significant decrease of relapse-free survival. Short tandem repeat profiling of the tumors showed absence of H1975 cells in sensitive tumors in dual inoculated animals, ruling out cell migration as the mechanism of resistance. This result can also not be explained by transfer of mutated DNA from resistant to sensitive cells because high-end sequencing detected the presence of the T790M mutation only in few sensitive tumors from dual inoculated mice and with an extremely low allele frequency ( Citation Format: Susana Junqueira-Neto, Ana Rita Oliveira, Joana Marques, Sónia Melo, José Luís Costa, José Carlos Machado. Resistance to anti-EGFR therapy can spread horizontally among cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1099.

Exosomes are a subclass of extracellular vesicles involved in intercellular communication that are released by all cell types, including cancer cells. Cancer exosomes carry malignant information in the form of proteins, lipids, and nucleic acids that can reprogram recipient cells. Exosomes have emerged as putative biological mediators in cancer contributing to major steps of disease progression. A leading role exists for cancer exosomes in specific aspects of tumor progression: modulation of immune response, tumor microenvironment reprogramming, and metastasis. This review will address the functions attributed to cancer exosomes in these three aspects of cancer biology, highlighting recent advances and potential limitations. Finally, we explore alternative strategies to develop better models to study cancer exosomes biology. Cancer Res; 77(23); 6480–8. ©2017 AACR.

Genetic analyses of chromatin remodelers in cancer Laia S. Riudalbas1, Sónia A. Melo, Anna Portela & Manel Esteller. 1Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08907 L'Hospitalet, Barcelona, Catalonia, Spain Chromatin remodelers are ATP dependent proteins that enable dynamic access to packaged DNA and tailor nucleosome composition in chromosomal regions. These protein complexes have been shown to regulate a wide range of cellular processes, including transcription regulation, DNA-damage response and DNA replication. Being that some components of this remodeler machinery were already characterized as tumor suppressor genes and/or oncogenic, we can hypothesize that the dysregulation of any of these molecules in tumor cells with microsatellite instability (MSI+), that show a higher rate of insertions and deletions, can lead to neoplastic transformation. For that we decided to screen all the exonic mononucleotide repeats of some of the most important chromatin remodelers with ATPase activity in colorectal, gastric and endometrial cancer cell lines, on the search for frameshift mutations that could alter protein function. We have mainly analyzed the catalytic subunits of remodeling complexes because any alteration of these crucial proteins could drive into a tumorigenic process. Until now no alteration was found in the cancer cell lines studied. This could be underscoring the importance of these genes to normal cellular functioning being that their disruption could impair cell viability. This work was supported by Grants SAF2007-00027-65134, FIS PI08-0517, Consolider CSD2006-49, and CANCERDIP FP7-200620. L.S.R. is a research fellow of FIS - Instituto de Salud Carlos III, FI09/00218. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4887.