An In Vivo Inflammatory Loop Potentiates KRAS Blockade

Abstract

KRAS (KRAS proto-oncogene, GTPase) inhibitors perform less well than other targeted drugs in vitro and fail clinical trials. To investigate a possible reason for this, we treated human and murine tumor cells with KRAS inhibitors deltarasin (targeting phosphodiesterase-δ), cysmethynil (targeting isoprenylcysteine carboxylmethyltransferase), and AA12 (targeting KRASG12C), and silenced/overexpressed mutant KRAS using custom-designed vectors. We showed that KRAS-mutant tumor cells exclusively respond to KRAS blockade in vivo, because the oncogene co-opts host myeloid cells via a C-C-motif chemokine ligand 2 (CCL2)/interleukin-1 beta (IL-1β)-mediated signaling loop for sustained tumorigenicity. Indeed, KRAS-mutant tumors did not respond to deltarasin in C-C motif chemokine receptor 2 (Ccr2) and Il1b gene-deficient mice, but were deltarasin-sensitive in wild-type and Ccr2-deficient mice adoptively transplanted with wild-type murine bone marrow. A KRAS-dependent pro-inflammatory transcriptome was prominent in human cancers with high KRAS mutation prevalence and poor predicted survival. Our findings support that in vitro cellular systems are suboptimal for anti-KRAS drug screens, as these drugs function to suppress interleukin-1 receptor 1 (IL1R1) expression and myeloid IL-1β-delivered pro-growth effects in vivo. Moreover, the findings support that IL-1β blockade might be suitable for therapy for KRAS-mutant cancers.

The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC

“…Combination approaches especially targeting the upstream and downstream of RAS-MAPK pathway to maximize the vertical inhibition [53,58,80,87,89,90], as well as targeting PI3K-AKT pathway for parallel inhibition [77] are found to be effective. Finally, as KRAS G12C mutation is involved in a proinflammatory TME, dysregulated cell cycle and autophagy, combinatorial efficacy with immunotherapy, chemotherapy and autophagy inhibition is anticipated [5,42,91,[93][94][95].…”

“…Moreover, patients with the KRAS G12C mutation are typically subject to an immunosuppressive tumor microenvironment (TME) with a correlated increase in PD-L1 expression, and a decrease in the effectiveness of CD8+ due to downregulation of major histocompatibility complex (MHC) class I [5]. However, CT-26 mice treated with G12C inhibitors presented with a remodeled, proinflammatory TME marked by increased infiltration of CD4+ T cells, CD8+ T cells, CD19+ B cells, NK cells, dendritic cells, and M1-polarized macrophages relative to the non-treated mutant mice [5,42,[93][94][95]. Interestingly, the antitumor response created during KRAS inhibition treatment only became durable when supplemented with a PD-1 inhibitor [95].…”

Systemic BCG administration stimulates NK and T cell-mediated antitumor lung immunity and overcomes tumor resistance to immune checkpoint inhibition

“…During the last decade, targeting of the PD-1 / PD-L1 axis has become a ground-breaking hallmark in the treatment of different types of cancer, including lung tumors. We then aimed to explore whether IV BCG immunotherapy could improve the efficacy of ICIs targeting PD- We additionally explored an orthotopic model of lung cancer based on IV inoculation of Lewis Lung Carcinoma (LLC) cells, a Kras G12C /P53 WT cell line 38,39 that has been widely used as model of non-small cells lung cancer (NSCLC). We used a similar experimental schedule as in the B16-F10 model, administrating IV BCG at 7 days post tumor-cell inoculation.…”