Atebimetinib对MEK的深度周期性抑制可约束RAS突变肿瘤患者MAPK轴的适应性与获得性改变

Purpose: This study characterized acquired molecular alteration patterns arising in patients with RAS mutant tumors during treatment with the pulsatile MEK inhibitor atebimetinib (IMM-1-104), a once daily oral drug in clinical development that drives Deep Cyclic Inhibition (DCI) to modulate the MAPK pathway without continuous suppression. Methods: 64 patients with RAS-mutant, advanced solid tumors received monotherapy atebimetinib, and serial circulating tumor DNA (ctDNA) analyses were performed to assess emergent genomic alterations detected with treatment over time. The evaluable patient population included a broad range of tumor types, disease stages and prior therapeutic exposures. Results: Atebimetinib treatment did not lead to meaningful reactivation of the RAS/MAPK pathway, as canonical resistance events such as secondary RAS mutations, RAS-mutant allele amplification, or activating RAF variants were rarely observed. These events occurred less frequently than reported under continuous MEK, ERK, KRAS-selective, or pan-RAS inhibition, suggesting that intermittent DCI-based MAPK suppression reduces selective pressure for classical pathway signaling restoration. Rather than reestablishing MAPK dependence, emergent acquired mutation patterns were heterogeneous. Tumors frequently carried alterations spanning multiple pathway classes, for example combinations of cell-cycle deregulation, growth-factor and PI3K signaling, and transcriptional or epigenetic remodeling, including MYC-linked programs, without convergence on a single bypass mechanism. This pattern is consistent with distributed multipathway adaptive changes rather than reliance on a discrete secondary driver. Conclusions: Atebimetinib-treated patient data demonstrate that deep, pulsatile MEK inhibition prevents the sustained loss of adaptive feedback commonly observed with chronic MAPK-pathway blockade, thereby reducing selective pressure for MAPK-reactivating resistance mechanisms. The resulting shift toward non-MAPK pathways suggests that atebimetinib's DCI mechanism, unlike chronic target engagement, limits MAPK-axis evolution. The low incidence of RAS/MAPK reactivation events supports evaluation of atebimetinib as a preferential combination backbone with either mutant-selective RAS inhibitors or mechanistically complementary therapies to enhance response durability and constrain RAS/MAPK pathway-mediated escape.