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.
Highlights
Since its discovery, the Kirsten rat sarcoma virus (KRAS) proto-oncogene GTPase has become the holy grail of anticancer therapy [1,2]
Using transcriptome analyses of cell lines expressing endogenous or exogenous wild-type or mutant Kras alleles, Ccr2 (C-C motif chemokine receptor 2) and Il1b gene-deficient mice, as well as adoptive bone marrow transfer, we show that mutant KRAS established a proinflammatory C-motif chemokine ligand 2 (CCL2) (C-C motif chemokine ligand 2)/IL-1β-mediated signaling loop to host myeloid cells in vivo, which is required for KRAS-mediated tumorigenicity and, importantly, for specific KRAS inhibitor efficacy
We initially investigated the cellular responses of a battery of human and murine cell lines with known KRAS/Kras (KRAS proto-oncogene, GTPase) mutation status [4,15–17]
Summary
The Kirsten rat sarcoma virus (KRAS) proto-oncogene GTPase (encoded by the human KRAS and the murine Kras genes) has become the holy grail of anticancer therapy [1,2]. Full KRAS GTPase activity and downstream signaling prerequires its integration into the cell membrane, which is facilitated by the post-translational lipidation and membrane transport of KRAS by various enzymes, such as farnesyltransferase (FT), geranylgeranytransferase (GGT), isoprenylcysteine carboxyl methyltransferase (ICMT), phosphodiesterase-δ (PDEδ), and others [3,5] To this end, therapeutic attempts to inhibit KRAS lipidation by targeting FT/GGT/ICMT were recently coupled with the development of PDEδ blockers and of allosteric and covalent inhibitors of mutated KRASG12C [6–9]. In addition to molecular structural considerations [5], the mode of KRAS oncogenic functions could be a reason for this To this end, Janes and collaborators recently reported a discordance between the in vitro and the in vivo effects of a newly developed covalent KRASG12C inhibitor [9]. Our data show that intact inflammatory tumor-to-host interactions were required for full KRAS inhibitor efficacy and imply that in vitro drug screens might not be optimal for KRAS inhibitor discovery
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