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》

ADT-1004: A First-in-Class, Orally Bioavailable Selective pan-RAS Inhibitor for Pancreatic Ductal Adenocarcinoma.

Reddy Bandi DS ，Nagaraju GP ，Sarvesh S ，Carstens JL ，Foote JB ，Graff EC ，Fang YD ，Keeton AB ，Chen X ，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 ... -  《-》

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 ... -  《-》

Pancreatic cancer-derived extracellular vesicles enhance chemoresistance by delivering KRAS(G12D) protein to cancer-associated fibroblasts.

KRAS mutations are instrumental in the development and progression of pancreatic ductal adenocarcinoma (PDAC). Nevertheless, the efficacy of direct targeting of KRAS mutations to inhibit tumor development remains doubtful. It is therefore necessary to gain a deeper insight into the mechanism in which KRAS mutations influence the effectiveness of clinical treatments. In this study, KRASG12D protein was detected in cancer-associated fibroblasts (CAFs) from clinical samples of PDAC. In vitro experiments demonstrated that KRASG12D protein in CAFs was not expressed from its own mutant gene but was derived from the ingestion of tumor cell-derived extracellular vesicles (EVs). The presence of KRASG12D protein in CAFs resulted in enhanced proliferation and migration. Furthermore, KRASG12D-containing CAFs were observed to promote tumor chemoresistance to gemcitabine treatment both in vitro and in vivo. Application of a KRAS mutation-specific inhibitor, MRTX1133, has been demonstrated to reverse chemoresistance in PDAC. Moreover, clinical data suggest that patients with KRAS mutations have poorer prognosis following adjuvant chemotherapy. These findings elucidate the mechanism by which oncogenic KRAS mutations promote cancer chemoresistance and remodel tumor environment in a non-autonomous manner, suggesting a novel strategy for targeting KRAS mutations to enhance chemosensitivity in PDAC.

Liu X ，Yang J ，Huang S ，Hong Y ，Zhu Y ，Wang J ，Wang Y ，Liang T ，Bai X ... -  《-》

Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer.

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+; Trp53LSL-R172H/+; p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, Cdk6, and Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies. Significance: Acquired resistance may limit the impact of KRAS inhibition in patients with PDAC. Using clinical samples and multiple preclinical models, we define heterogeneous genetic and non-genetic mechanisms of resistance to KRAS inhibition that may guide combination therapy approaches to improve the efficacy and durability of these promising therapies for patients. See related commentary by Marasco and Misale, p. 2018.

Dilly J ，Hoffman MT ，Abbassi L ，Li Z ，Paradiso F ，Parent BD ，Hennessey CJ ，Jordan AC ，Morgado M ，Dasgupta S ，Uribe GA ，Yang A ，Kapner KS ，Hambitzer FP ，Qiang L ，Feng H ，Geisberg J ，Wang J ，Evans KE ，Lyu H ，Schalck A ，Feng N ，Lopez AM ，Bristow CA ，Kim MP ，Rajapakshe KI ，Bahrambeigi V ，Roth JA ，Garg K ，Guerrero PA ，Stanger BZ ，Cristea S ，Lowe SW ，Baslan T ，Van Allen EM ，Mancias JD ，Chan E ，Anderson A ，Katlinskaya YV ，Shalek AK ，Hong DS ，Pant S ，Hallin J ，Anderes K ，Olson P ，Heffernan TP ，Chugh S ，Christensen JG ，Maitra A ，Wolpin BM ，Raghavan S ，Nowak JA ，Winter PS ，Dougan SK ，Aguirre AJ ... -  《-》