ADT-007:一种机制独特的泛 RAS 抑制剂,具有逃避其他 RAS 抑制剂共有的获得性耐药的能力

Gain-of-function mutations in RAS genes are the most prevalent oncogenic mutations responsible for about one-third of all human malignancies. Despite decades of research, direct targeting of RAS remains a major clinical challenge as RAS inhibitors recently FDA-approved or in clinical trials appear to have limited efficacy due to the emergence of acquired resistance. We recently described a mechanistically distinct pan-RAS inhibitor, ADT-007, that selectively kills cancer cells harboring activated RAS, whether driven by oncogenic mutations or activation by upstream receptor tyrosine kinase signaling. ADT-007 potently inhibited the growth of an array of cancer cell lines harboring various RAS mutations or activated RAS with low nM IC 50 values. In contrast, cancer cells with downstream RAF mutations or cells of normal tissues were essentially insensitive. Cellular, biochemical, and biophysical studies demonstrated that ADT-007 binds nucleotide-free RAS to block GTP loading and activation of the MAPK/AKT signaling pathway, resulting in mitotic arrest and apoptosis. ADT-007's unique selectivity was attributed to metabolic detoxification by glucuronidation from UDP-glucuronosyltransferases (UGTs), which we found to be enriched in normal cells compared with RAS-mutant cancer cells. Notably, ADT-007 induced apoptosis and caused nearly complete inhibition of colony formation of Mia-PaCa-2 human pancreatic cell line, while the pan-KRAS inhibitor, BI-2865, and the pan-RAS inhibitor, RMC-6236, did not induce apoptosis, but only suppressed proliferation and marginally inhibited colony formation under the same conditions. Furthermore, RAS mutant colon and pancreatic cancer cells did not develop resistance to ADT-007 under chronic exposure, in contrast to sotorasib, BI-2865, and RMC-6236, which readily produced cultures that were essentially unresponsive to the inhibitor they were exposed to. Moreover, the resistant cell lines exhibited cross-resistance to mechanistically distinct classes of RAS inhibitors, including pan-KRAS, pan-RAS, and allele-specific KRAS inhibitors, but not to ADT-007 or a second-generation inhibitor, ADT-030. These observations suggest a shared mechanism of acquired resistance that may limit the efficacy of currently known RAS inhibitors (approved or in development). An orally bioavailable prodrug of ADT-007, ADT-1004, demonstrated favorable tolerability and suppressed tumor growth in orthotopic and patient-derived xenograft models of pancreatic cancer, accompanied by reductions in activated RAS and p-ERK levels. Consistent with resistance experiments, ADT-1004 displayed superior efficacy than sotorasib or adagrasib in a xenograft model using a resistant MIA-PaCa-2. These findings support further development of ADT-1004 that holds promise for broad and durable efficacy against RAS-driven cancers.