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Abstract The Australian Zero Childhood Cancer (ZERO) program and German INFORM registry - the largest precision medicine initiatives for childhood cancers - conduct comprehensive tumour molecular characterisation and ex vivo drug sensitivity profiling (DSP) to support clinical treatment decision-making. Both programs have identified frequent alterations in the mitogen-activated protein kinase (MAPK) pathway, leading to the recommendation of treatment with a mitogen-activated protein kinase kinase (MEK) inhibitor. Interestingly, ex vivo DSP indicates that tumors without MAPK aberrations can also respond to MEK inhibition, revealing potential broader therapy applications. Although promising, clinical responses to single MEK inhibitor treatment guided by predictive MAPK alterations have been disappointing, highlighting the need for effective combination strategies to overcome resistance. Here, we compare vertical blockade of the MAPK pathway with horizontal inhibition of the MAPK and phosphatidylinositol-3 kinase (PI3K) pathways to enhance the efficacy of MEK inhibitors for childhood cancers.Ex vivo testing was conducted on 68 samples from high-risk pediatric cancer patients enrolled in ZERO, representing all major cancer types. Tumor samples were treated with the MEK inhibitors trametinib and/or pimasertib, the rapidly accelerated fibrosarcoma (RAF) inhibitor tovorafenib, and the PI3K inhibitor paxalisib, either alone or in combination. Efficacy was integrated with matched molecular profiling data. Vertical blockade of the MAPK pathway by combined MEK and RAF inhibition demonstrated strong synergy (highest Loewe synergy score 20) at clinically relevant concentrations in 23 out of 58 samples, resulting in at least a 75% reduction in cell viability in 17 of these 23 samples. Western blot analysis confirmed MAPK pathway reactivation upon single-agent MEK inhibitor treatment. Synergy was particularly notable in sarcoma samples with homozygous loss of function (LoF) of the neurofibromin 1 (NF1) gene, consistent with observations for another sarcoma sample with NF1 LoF derived from a patient enrolled in the INFORM registry. Among 17 diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG) samples, 12 exhibited strong synergy and high efficacy in the absence of MAPK alterations. These included two cases with PI3K pathway-activating mutations in PIK3R1, a gene previously associated with activated MAPK signalling. No synergism was observed between horizontal inhibition of the MAPK and PI3K pathways in these two cases. Combined MAPK and PI3K pathway inhibition was only strongly synergistic in one rhabdomyosarcoma sample without alterations in either pathway. Our findings indicate that vertical blockade of the MAPK pathway is a promising strategy to enhance the efficacy of MEK inhibitors for brain tumor and sarcoma subgroups, which otherwise face dismal outcomes. If validated in vivo, combined MEK and RAF inhibition will be included as an arm in the recently opened OPTIMISE trial. Citation Format: Gabor Tax, Jie Mao, Roxanne Cadiz, Tamar Barhen, Jinhan Xie, Jessica Harris, Mirae Bae, Lauren M. Brown, Karina Pazaky, Andrew J. Gifford, Chelsea Mayoh, Marion K. Mateos, Heike Peterziel, Ina Oehme, David S. Ziegler, Maria Tsoli, Ben Rayner, Paul G. Ekert, M. Emmy M. Dolman. Expanding therapeutic horizons: Unleashing the untapped potential of MEK inhibitor treatment in pediatric cancers abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B003.
Tax et al. (Thu,) studied this question.