KRAS as a modulator of the inflammatory tumor microenvironment: therapeutic implications

KRAS mutations are one of the most frequent oncogenic mutations of all human cancers, being more prevalent in pancreatic, colorectal, and lung cancers. Intensive efforts have been encouraged in order to understand the effect of KRAS mutations, not only on tumor cells but also on the dynamic network composed by the tumor microenvironment (TME). The relevance of the TME in cancer biology has been increasing due to its impact on the modulation of cancer cell activities, which can dictate the success of tumor progression. Here, we aimed to clarify the pro- and anti-inflammatory role of KRAS mutations over the TME, detailing the context and the signaling pathways involved. In this review, we expect to open new avenues for investigating the potential of KRAS mutations on inflammatory TME modulation, opening a different vision of therapeutic combined approaches to overcome KRAS-associated therapy inefficacy and resistance in cancer.This work was financed by the Portuguese Foundation for Science and Technology (Fundacao para a Ciencia e a Tecnologia, FCT) within the scope of two PhD grants, SFRH/BD/140137/2018 attributed to FP and SFRH/BD/142486/2018 attributed to AF. A.P. acknownledges FCT within the scope of the project PTDC/QUIQIN/28662/2017. A.P. and M.J.S. also acknowledge the support of the CBMA strategic programme "Contrato-Programa" UIDB/04050/2020 funded by national funds through the FCT I.P. C.A.R. acknowledges the project Norte-01-0145-FEDER-000051-"Cancer Research on Therapy Resistance: From Basic Mechanisms to Novel Targets", supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). M.J.O. acknowledges FEDER funds through COMPETE 2020-Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, Portuguese funds through FCT/Ministerio da Ciencia, Tecnologia e do Ensino Superior in the framework of the project POCI-01-0145-FEDER-31859/2017