Enhancing anticancer activity of checkpoint immunotherapy by targeting RAS

Abstract

Approximately 30% of human cancers harbor a gain-in-function mutation in the RAS gene, resulting in constitutive activation of the RAS protein to stimulate downstream signaling, including the RAS-mitogen activated protein kinase pathway that drives cancer cells to proliferate and metastasize. RAS-driven oncogenesis also promotes immune evasion by increasing the expression of programmed cell death ligand-1, reducing the expression of major histocompatibility complex molecules that present antigens to T-lymphocytes and altering the expression of cytokines that promote the differentiation and accumulation of immune suppressive cell types such as myeloid-derived suppressor cells, regulatory T-cells, and cancer-associated fibroblasts. Together, these changes lead to an immune suppressive tumor microenvironment that impedes T-cell activation and infiltration and promotes the outgrowth and metastasis of tumor cells. As a result, despite the growing success of checkpoint immunotherapy, many patients with RAS-driven tumors experience resistance to therapy and poor clinical outcomes. Therefore, RAS inhibitors in development have the potential to weaken cancer cell immune evasion and enhance the antitumor immune response to improve survival of patients with RAS-driven cancers. This review highlights the potential of RAS inhibitors to enhance or broaden the anticancer activity of currently available checkpoint immunotherapy.

Targeting the undruggable oncogenic KRAS: the dawn of hope

“…Moreover, this approach improved the diversity of the peripheral T cell receptor (TCR) repertoire of patients and was associated with longer survival ( 78 ). Several studies have focused on immune modulation by oncogenic KRAS and checkpoint inhibitors in lung, pancreatic, and colon cancers, which are reviewed elsewhere ( 74 , 79 , 80 ).…”

The AMPK-HOXB9-KRAS axis regulates lung adenocarcinoma growth in response to cellular energy alterations

“…KRAS regulates the nutrient stress response in such patients, increasing glucose uptake and glycolysis (Ying et al, 2012) even in the presence of abundant oxygen (the Warburg effect). This modulates the redox balance, stimulates glutamine catabolism, and increases fatty acid uptake for macromolecular synthesis (Padanad et al, 2016;Skoulidis and Heymach, 2019;Ward et al, 2020). Mutations in both Kras and LKB1, a tumor suppressor and the principal upstream kinase of AMPK activation (Faubert et al, 2020;Hardie et al, 2012), respectively trigger more serious metastases, therapy resistance, and poor prognosis in patients with LUAD (Calles et al, 2015;Chen et al, 2012;Ji et al, 2007).…”

Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA Analysis

“…Activation of the JAK-STAT signaling pathway inhibits cytotoxic T lymphocytes and counteracts the antitumor effects of anti-PD-1 immunotherapy in pancreatic cancer ( 60 ). RAS-related oncogenesis could increase the level of PD-L1, eliminate antigen presentation, and alter the expressions of cytokines, thus leading to immune evasion and immunotherapy resistance ( 61 ). The research implies a close relationship between immunotherapy resistance and cancer stemness.…”