The JAK/STAT pathway is frequently dysregulated in PTCL and CTCL, resulting in uncontrolled signaling, cell proliferation, and disease progression. Recently, the JAK/STAT pathway has emerged as a promising therapeutic target, with inhibitors such as ruxolitinib and golidocitinib demonstrating clinical activity. Ruxolitinib was the first JAK inhibitor approved for cancer treatment in the U.S, and remains one of the most widely used; however, its response rates in PTCL and CTCL remain modest, and the clinical benefits are often transient.
To identify synergistic partners for ruxolitinib, we conducted a genome-wide CRISPR interference (CRISPRi) screen in CTCL cell lines, HH and Hut78. The screen identified histone modifications, particularly acetylation and methylation, as key mechanisms enhancing CTCL cell sensitivity to ruxolitinib. These findings were validated using histone-modifying agents, romidepsin and 5-azacitidine, both of which enhanced the antitumor activity of ruxolitinib in HH and Hut78.
Furthermore, similar synergy was observed with golidocitinib, a recently approved JAK1 inhibitor for PTCL in China, indicating an on-target class effect of synergy between JAK/STAT inhibition and histone-modifying agents.
Importantly, these results were validated in primary human CTCL cells derived from patient-derived xenograft models. Synergistic growth inhibition and apoptosis induction were observed with ruxolitinib or golidocitinib in combination with either romidepsin or 5-azacitidine, demonstrating the clinical relevance of this approach.
In conclusion, genome-wide CRISPRi identified rational combination partners for JAK/STAT pathway inhibition. Validation of these findings in primary CTCL tumor cells underscores the translational potential of this strategy. Ongoing therapeutic trials with PDX animals will further investigate these promising findings.
