A Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth and Induces Antitumor Immunity in Gastrointestinal Cancer.

Activated RAS is a common driver of cancer that was considered undruggable for decades. Recent advances have enabled the development of RAS inhibitors, but the efficacy of these inhibitors remains limited by resistance. In this study, we developed a pan-RAS inhibitor, ADT-007, (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide, that binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 potently inhibited the growth of RAS-mutant cancer cells irrespective of the RAS mutation or isozyme. Wild-type RAS (RASWT) cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RASWT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, whereas insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases that were expressed in RASWT and normal cells but repressed in RAS-mutant cancer cells. ADT-007 displayed unique advantages over KRAS mutant-specific, pan-KRAS, and pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms that lead to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immunocompetent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancers. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth. Thus, ADT-007 has the potential to address the complex RAS mutational landscape of many human cancers and to improve treatment of RAS-driven tumors. Significance: ADT-007, a first-in-class pan-RAS inhibitor, has unique selectivity for cancer cells with mutant RAS or activated RAS protein and the capability to circumvent resistance to suppress tumor growth, supporting further development of ADT-007 analogs.

Foote JB ，Mattox TE ，Keeton AB ，Chen X ，Smith FT ，Berry K ，Holmes TW ，Wang J ，Huang CH ，Ward A ，Mitra AK ，Ramirez-Alcantara V ，Hardy C ，Fleten KG ，Flatmark K ，Yoon KJ ，Sarvesh S ，Nagaraju GP ，Bandi DSR ，Maxuitenko YY ，Valiyaveettil J ，Carstens JL ，Buchsbaum DJ ，Yang J ，Zhou G ，Nurmemmedov E ，Babic I ，Gaponeko V ，Abdelkarim H ，Boyd MR ，Gorman G ，Manne U ，Bae S ，El-Rayes BF ，Piazza GA ... -  《-》

A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer.

Foote JB ，Mattox TE ，Keeton AB ，Chen X ，Smith F ，Berry KL ，Holmes T ，Wang J ，Huang CH ，Ward AB ，Mitra AK ，Ramirez-Alcantara V ，Hardy C ，Fleten KG ，Flatmark K ，Yoon KJ ，Sarvesh S ，Nagaraju GP ，Bandi DSR ，Maxuitenko YY ，Valiyaveettil J ，Carstens JL ，Buchsbaum DJ ，Yang J ，Zhou G ，Nurmemmedov E ，Babic I ，Gaponenko V ，Abdelkarim H ，Boyd MR ，Gorman GS ，Manne U ，Bae S ，El-Rayes BF ，Piazza GA ... -  《-》

ADT-1004: a first-in-class, oral pan-RAS inhibitor with robust antitumor activity in preclinical models of pancreatic ductal adenocarcinoma.

Oncogenic KRAS mutations occur in nearly, 90% of patients with pancreatic ductal adenocarcinoma (PDAC). Targeting KRAS has been complicated by mutational heterogeneity and rapid resistance. We developed a novel pan-RAS inhibitor, ADT-1004 (an oral prodrug of ADT-007) and evaluated antitumor activity in murine and human PDAC models. Murine PDAC cells with KRASG12D mutation (KPC-luc or 2838c3-luc) were orthotopically implanted into the pancreas of C57BL/6J mice, and four PDX PDAC tumors with KRAS mutations were implanted subcutaneously in NSG mice. To assess potential to overcome RAS inhibitor resistance, parental and resistant MIA PaCa-2 PDAC cells (KRASG12C mutation) were implanted subcutaneously. Subcutaneously implanted RASWT BxPC-3 cells were used to assess the selectivity of ADT-1004. ADT-1004 potently blocked tumor growth and RAS activation in mouse PDAC models without discernable toxicity with target engagement and reduced activated RAS and ERK phosphorylation. In addition, ADT-1004 suppressed tumor growth in PDX PDAC models with KRASG12D, KRASG12V, KRASG12C, or KRASG13Q mutations and increased CD4+ and CD8+ T cells in the TME consistent with exhaustion and increased MHCII+ M1 macrophage and dendritic cells. ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models resistant to these KRASG12C inhibitors and MRTX1133 resistant KRASG12D mutant cells. As evidence of selectivity for tumors with mutant KRAS, ADT-1004 did not impact the growth of tumors from RASWT PDAC cells. ADT-1004 has strong antitumor activity in aggressive and clinically relevant PDAC models with unique selectivity to block RAS-mediated signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.

Bandi DSR ，Nagaraju GP ，Sarvesh S ，Carstens JL ，Foote JB ，Graff EC ，Fang YD ，Keeton AB ，Chen X ，Valiyaveettil J ，Berry KL ，Bae S ，Akce M ，Gorman G ，Yoon KJ ，Manne U ，Boyd MR ，Buchsbaum DJ ，Azmi AS ，Maxuitenko YY ，Piazza GA ，El-Rayes BF ... -  《Molecular Cancer》

RAS mutation-specific signaling dynamics in response to paralog- and state- selective RAS inhibitors.

Baars B ，Orive-Ramos A ，Kou Z ，Gaire B ，Desaunay M ，Adamopoulos C ，Aaronson SA ，Wang S ，Gavathiotis E ，Poulikakos PI ... -  《-》

Enhancing efficacy of the MEK inhibitor trametinib with paclitaxel in KRAS-mutated colorectal cancer.

Ghosh S ，Fan F ，Powell R ，Park YS ，Stephan C ，Kopetz ES ，Ellis LM ，Bhattacharya R ... -  《-》