Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

Abstract

Current evidence strongly suggests that cancer cells depend on the microenvironment in order to thrive. In fact, signals from the surrounding tumor microenvironment are crucial for cancer cells´ aggressiveness, altering their expression profile and favoring their metastatic potential. As such, targeting the tumor microenvironment to impair cancer progression became an attractive therapeutic option. Interestingly, it has been shown that oncogenic KRAS signaling promotes a pro-tumorigenic microenvironment, and the associated crosstalk alters the expression profile of cancer cells. These findings award KRAS a key role in controlling the interactions between cancer cells and the microenvironment, granting cancer a poor prognosis. Given the lack of effective approaches to target KRAS itself or its downstream effectors in the clinic, exploring such interactions may open new perspectives on possible therapeutic strategies to hinder mutant KRAS tumors. This review highlights those communications and their implications for the development of effective therapies or to provide insights regarding response to existing regimens.

Keywords: KRAS; cancer therapy; colorectal cancer; immunotherapy; lung cancer; pancreatic cancer; tumor microenvironment.

Figure 1

Strategies to target mutant KRAS cells. The lack of efficient therapies targeting mutant KRAS tumors represents an unmet clinical need. Several strategies have already been tested or are currently under development. Inhibitors of KRAS downstream effector molecules (e.g., RAF, MEK, PI3K) did not result in significant clinical benefit as standalone treatments, but their use in combination with receptor tyrosine kinase (RTK) inhibition has been shown to induce favorable antitumoral responses. The development of KRAS direct inhibitors represents a major breakthrough in the field, particularly of those targeting specific mutant forms, such as the G12C mutation, which are currently in clinical trials. Moreover, several other strategies under study aim to identify synthetic lethal interactors of KRAS, to impair KRAS post-translational modifications interfering with its subcellular localization, and to hamper the mechanisms used by mutant cells to obtain nutrients and energy.

Figure 2

KRAS-induced immune-suppressive microenvironment. Mutant (mut)KRAS cells have been associated with decreased major histocompatibility class I (MHCI) expression, representing an impaired capacity to present antigens. Furthermore, the upregulation of programmed cell death ligand 1 (PD-L1) leads to immune evasion by inhibiting T-cell recognition. In these cells, the expression and secretion of several inflammatory cytokines is also recognized as being increased. Chemokine C-X-C ligand 3 (CXCL3) binds to its receptor chemokine C-X-C receptor 2 (CXCR2) on myeloid-derived suppressor cells (MDSCs) contributing to the maintenance and recruitment of these immune suppressive cells. In addition, granulocyte macrophage colony-stimulating factor (GM-CSF) is responsible for the accumulation of MDSCs in the tumor microenvironment. Moreover, the increased secretion of interleukin (IL)-10 and Transforming growth factor beta 1 (TGFβ1) induce the conversion of CD4+ CD25− T-cells into FOXP3+/CTLA4+/CD122+ T regulatory cells (Tregs) promoting immune suppression.