Impact of alternative splicing on mechanisms of resistance to anticancer drugs Reviejo, María Martínez Augustín, María Olga Sánchez De Medina López-Huertas, Fermín Alternative splicing Chemoresistance Chemotherapy Pharmacoresistance Tumor Spliceosome This study was funded by the CIBERehd (EHD15PI05/2016) and "Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III", Spain (PI16/00598 and PI19/00819, co-funded by European Regional Development Fund/European Social Fund, "Investing in your future"); Spanish Ministry of Economy, Industry and Competitiveness (SAF201675197-R, SAF2017-88457-R, AGL2017-85270-R); "Junta de Castilla y Leon" (SA063P17); "Junta de Andalucia (CTS235, CTS164); AECC Scientific Foundation (2017/2020), Spain; "Proyectos de Investigacion. Modalidad C2", University of Salamanca (18.K137/463AC01 and 18. K140/463AC01); "Centro Internacional sobre el Envejecimiento" (OLDHEPAMARKER, 0348_CIE_6_E), Spain and Fundacion University of Salamanca, Spain (PC-TCUE18-20_051); Fundacio Marato TV3 (Ref. 201916-31). M.R. was supported by a predoctoral scholarships (FPU) funded by the Ministry of Science, Innovation and Universities, Spain. A shared characteristic of many tumors is the lack of response to anticancer drugs. Multiple mechanisms of pharmacoresistance (MPRs) are involved in permitting cancer cells to overcome the effect of these agents. Pharmacoresistance can be primary (intrinsic) or secondary (acquired), i.e., triggered or enhanced in response to the treatment. Moreover, MPRs usually result in the lack of sensitivity to several agents, which accounts for diverse multidrug-resistant (MDR) phenotypes. MPRs are based on the dynamic expression of more than one hundred genes, constituting the so-called resistome. Alternative splicing (AS) during pre-mRNA maturation results in changes affecting proteins involved in the resistome. The resulting splicing variants (SVs) reduce the efficacy of anticancer drugs by lowering the intracellular levels of active agents, altering molecular targets, enhancing both DNA repair ability and defensive mechanism of tumors, inducing changes in the balance between pro-survival and pro-apoptosis signals, modifying interactions with the tumor microenvironment, and favoring malignant phenotypic transitions. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the impact of AS on MPR in cancer cells. 2021-12-07T08:04:59Z 2021-12-07T08:04:59Z 2021-10-19 journal article Maria Reviejo... [et al.]. Impact of alternative splicing on mechanisms of resistance to anticancer drugs, Biochemical Pharmacology, Volume 193, 2021, 114810, ISSN 0006-2952, [https://doi.org/10.1016/j.bcp.2021.114810] http://hdl.handle.net/10481/71900 10.1016/j.bcp.2021.114810 eng http://creativecommons.org/licenses/by-nc-nd/3.0/es/ open access Atribución-NoComercial-SinDerivadas 3.0 España Elsevier