Therapeutically targeting mutant KRAS represents a clinically validated approach for the treatment of solid tumors, including lung, colon, and pancreatic cancers. The approval of covalent KRASG12C inhibitors, such as sotorasib and adagrasib, has fueled intense interest in expanding KRAS-directed therapies to mutations beyond KRAS G12C, such as KRAS G12D, KRAS G12V, and KRAS G13D. Here, we describe the structure- and property-based design of reversible inhibitors of diverse oncogenic mutants of KRAS, leading to AM-2383, a pan-KRAS inhibitor that blocks signaling via both the GDP(off)- and GTP(on)-bound states of KRAS, while sparing the closely related RAS isoforms HRAS and NRAS. AM-2383 disrupts signaling downstream of KRAS, potently suppressing the growth of KRAS G12D and KRAS G12V tumor xenografts following oral administration. AM-2383 represents an important proof-of-concept that structural insights from prior covalent KRASG12C inhibitors can be leveraged in the design of efficacious and well-tolerated inhibitors of diverse KRAS mutations.
Ryan P Wurz, Jennifer R Allen, John G. Allen et al.· Journal of Medicinal Chemist...· 0 citations
While mutant-specific KRAS inhibitors are approved to treat cancer, a deeper understanding of intratumoral changes driven specifically by KRAS inhibition is needed to maximize therapeutic responses. Here, we used single-cell RNA-seq, flow cytometry, and spatial transcriptomics to distinguish mechanisms of tumor control after KRASG12C inhibition (KRAS(G12C)i) or MEK inhibition (MEKi). Despite both inhibiting the MAPK pathway, KRAS(G12C)i and MEKi drive the adaptation of distinct neoplastic cell fates affecting metabolism and cell cycle regulation, and additive tumor suppression is observed after co-administration. KRAS(G12C)i results in the emergence of a specific, cDC1-driven mature conventional dendritic cell (cDC) state. Co-culture of treated neoplastic cells with cDC1s is sufficient to upregulate maturation markers such as CCR7, intercellular communication analyses suggest activation is augmented through non-immune mediators. Both KRAS(G12C)i and MEKi increase infiltration of cytotoxic T cells, but MEKi, which also targets non-malignant cells, is associated with a reduced capacity for T-cell proliferation and degranulation, consistent with distinct adaptive immune activation mechanisms. We observe that combination treatment of KRAS(G12C)i with anti-PD-1 immunotherapy further expands effector T-cell states, increases clonal persistence, and induces pro-inflammatory macrophages associated with higher overall survival that were largely absent after KRAS(G12C)i alone. Furthermore, combination treatment enhances intercellular communication networks among non-PD-1+ expressing cells that can perpetuate cDC activation. Our findings delineate distinct tumor and immune responses to KRAS and MEK inhibition and identify molecular features of the responding tumor microenvironment that may be leveraged to improve therapeutic efficacy.
Daniel R Lu, T. Osgood, Shining Ma et al.· Cancer immunology research· 0 citations
