Remission instead of eradication? MEK inhibition in primary refractory childhood LCH

Abstract Background Langerhans Cell Histiocytosis (LCH) is a clonal myeloid neoplasm caused by activating somatic mutations in the MAPK signaling pathway, detectable in approximately 85% of pediatric cases. While mutations in BRAFV600E and MAP2K1 are most common, rare non-V600E variants have also been described, including in-frame deletions in BRAF and activating ARAF mutations. These alterations exhibit distinct kinase behavior, often inducing RAS-independent dimer-driven MAPK activation and show resistance to standard BRAF inhibitors. In infants with risk organ involvement, failure rates with conventional chemotherapy remain high, necessitating individualized, mutation-specific treatment strategies. Patient and Methods We report on a 9-month-old infant with multisystemic LCH (thymus and cervical lymph nodes) who progressed under vinblastin/prednisone and did not respond to second-line cytarabine/vincristine therapy. Whole-exome sequencing revealed a rare BRAF in-frame deletion (p.N488_P490) affecting the αC-helix of the kinase domain, resulting in constitutive MAPK signaling independent of RAS. This class confers resistance to first-and second generation BRAF inhibitors (e.g., Vemurafenib, Dabrafenib), which preferentially target monomeric BRAFV600E but not dimer-dependent BRAF. Functional ex vivo drug sensitivity profiling demonstarted superior tumor cell cytotoxicity of cobimetinib compared to other tested agents, including BRAF inhibitors and alternative MEK1/2 inhibitors, such as trametinib and selumetinib. These results confirmed the treatment with cobimetinib (0.8mg/kgBW/day). Clinical Course Cobimetinib led to rapid tumor regression (75% after 3.5 weeks and 94% after 13 weeks) with complete radiological remission after 6 months. Treatment was discontinued after a further six months of sustained response. However, seven months after cessation of therapy, a locoregional thymic and cervical lymph node recurrence occured, which again responded rapidly to the re-administration of cobimetinib. The treatment was well tolerated in all phases, with no significant toxicities observed. Discussion Therapeutic goals in LCH should go beyond clinical remission and include eradication of the clonal population to prevent long-term late complications, especially CNS involvement. This case highlights the clinical relevance of mutation guided therapy and functional profiling in pediatric LCH: given the increasing number of available MAPK inhibitors (BRAFi,MEKi,ERKi), individualized selection is essential. Among MEK inhibitors, cobimetinib showed superior efficacy due to its high MEK1 selectivity and allosteric binding which fixes MEK1 in an inactive conformation. This pharmacodynamic profile is particularly advantageous in BRAF in-frame deletions with stronger dimer-driven MAPK flux which can bypass reversible inhibitors such as trametinib or selumetinib. Functional tests confirmed the superiority of cobimetinib in our case. Relapse after discontinuitation highlights a key limitation of MEK inhibition as monotherapy: persistent clonal cells may adopt a senescent phenotype, characterized by apoptosis resistance and Senescence-Associated Secretory Phenotype (SASP) driven inflammation . This senescence-associated microenvironment may sustain disease activity and increase risk of CNS involvement. New therapeutic strategies therefore aim to combine MEK inhibition with senolytic agents and/or mTOR inhibitors to eliminate senescent clones and suppresses SASP signaling. While most mechanistic data on this senescent model focus on BRAFV600E, similar MAPK-driven programs may also be present in non-V600E variants such as BRAF deletions and MAP2K1 mutations, as suggested by transcriptional profiling and preclinical studies. Conclusions Cobimetinib induced rapid, sustained and repeatable responses in treatment-resistant pediatric LCH with a non-V600E BRAF mutation. Its MEK1-selective, allosteric inhibition may offer superior pathway suppression in RAS-independent BRAF activation. However, the risk of clonal persistence underscores the need for integrated strategies. Future studies should investigate rational combinations of MEK inhibitors with senolytics and/or mTOR blockade to target both MAPK signaling and senescent cell survival, thereby suppressing SASP-related inflammation, aiming for durable molecular remission and neuroprotection.