Signalisation Spécifique à la Lignée et ciblage de PI3Kγ dans les leucémies aiguës myéloïdes

Acute myeloid leukemias (AML) are hematologic malignancies characterized by clonal proliferation of abnormal myeloid progenitors. The five-year overall survival rate for patients diagnosed with de novo AML is 30%. This rate falls below 10% in patients diagnosed after 60 years, partially driven by the inability of elderly patients to tolerate traditional chemotherapies (Shimony et al., 2023). Given that the median age at diagnosis is 68, dose-limiting toxicity is responsible for significant cancer-related mortality (Appelbaum et al., 2006). However, targeted treatments, designed to shut down specific, aberrantly- activated pathways, are generally well- tolerated, including in older patients (Kadia and Wei, 2022; Kantarjian et al., 2021; Shen et al., 2025). Unfortunately, most patients diagnosed with AML lack actionable mutations, underscoring the need to identify additional therapeutic targets. A cancer’s tissue-of-origin templates key features of its biology, implying that certain lineage-specific programs may be co- opted in neoplastic precursor cells to support tumorigenesis and tumor progression. An ideal lineage- restricted cancer therapeutic target would be a druggable protein that: (i) has pleiotropic regulatory functions, governing essential pro-survival processes in the target cancer tissue, and (ii) should display specific expression patterns that are confined to a narrow range of cell types. Inhibitors designed to selectively modulate tissue- selective isoforms of critical survival regulators could effectively impede the growth of cancer cells in these specific tissues without causing widespread toxicity. In this study we present the PI3Kγ isoform of PI3K as a tissue-specific dependency in myeloid cells, Phosphoinositide 3-kinase (PI3K) is a regulatory enzyme with pleiotropic, essential functions that is a frequently altered driver of malignant progression. PI3Kγ could be selectively targeted to target AML cells and avoid side effects in non-malignant tissues. Phosphoinositide 3-kinase (PI3K) is a regulatory enzyme with pleiotropic, essential functions that is a frequently altered driver of malignant progression. Alterations in PI3K catalytic isoforms and PTEN, are prevalent in various tumor types, prompting extensive efforts to develop inhibitors of PI3K and its downstream effectors (Hirai et al., 2010). Unfortunately, due to diffuse patterns of PI3K expression across non-malignant tissues, dose-limiting toxicities emerge secondary to their inhibition. One strategy is to target the essential enzyme, PI3K, in a tissue-specific manner based on isoform-dependency. Here, we show that the catalytic subunit of PI3Kγ, PIK3CG/p110γ and its cognate regulatory subunit PIK3R5/p101 form a signaling node responsible for AKT signaling downstream of GPCRs. Genetic loss of PIK3CG/ PIK3R5 expression causes cytotoxicity in AML cells as a result of its role as a signaling mediator which can be further potentiated in combination with existing AML therapy, venetoclax. Traditional small molecule inhibitors of PIK3CG were unable to mirror the cytotoxic effects of its genetic ablation. We hypothesized that continuous degradation of PIK3CG using a PROteolysis TArgeting Chimera (PROTAC) strategy would target the entire pro-survival function of PIK3CG and cause more effective inhibition of downstream signals. Indeed, the resulting heterobifunctional degrader molecule, ARM165, exhibited superior cytotoxic properties as compared to the traditional small molecule inhibitors in AML cells. ARM165 acts as a proof-of-concept that targeted degradation using PROTACs as compared to kinase inhibition using traditional small molecule inhibitors, can more effectively inhibit targets of interest. And this study highlights the potential of PI3Kγ as a lineage-specific therapy for the treatment of AML justifying further studies into the therapeutic targeting of PI3Kγ in this context.