Which molecular pathways (PAK1, Akt/mTOR, Wnt/β‑catenin) are most implicated in ivermectin’s anticancer activity and how do they vary by tumor type?
Executive summary
Preclinical evidence places PAK1 and its downstream Akt/mTOR axis as the single most consistently implicated route for ivermectin’s anticancer effects—especially in breast cancer where ivermectin promotes ubiquitin-mediated degradation of PAK1, reducing Akt phosphorylation and activating cytostatic autophagy [1] [2] [3]. Parallel but distinct modulation of Wnt/β‑catenin signaling is documented in models of metastasis and endocrine‑resistant breast and colorectal tumors, so the dominant pathway varies by tumor context and the anticancer phenotype under study (proliferation vs migration) [4] [5] [6].
1. PAK1 → Akt/mTOR: the clearest mechanistic story, strongest in breast models
Multiple groups independently report that ivermectin downregulates PAK1 and thereby reduces Akt phosphorylation, blocking the Akt/mTOR pathway and inducing autophagy that suppresses tumor growth; this mechanism is described in breast cancer cell lines and xenografts and is the central experimental finding in Cancer Research and supporting Autophagy publications [1] [2] [3]. Reviews synthesize these results and point to PAK1 as a linchpin connecting ivermectin to autophagy and growth inhibition across several tumor types, noting PAK1’s role as an Akt‑binding protein that stimulates Akt activation [7] [8].
2. How that PAK1→Akt/mTOR signature differs by tumor type
Breast cancer: direct, in vivo evidence shows ivermectin promotes ubiquitin‑proteasome degradation of PAK1 with downstream Akt/mTOR inhibition and cytostatic autophagy in xenografts [1] [2]. Ovarian and NF2 (merlin‑deficient) models: earlier studies report ivermectin inactivates PAK1 and blocks PAK1‑dependent growth in ovarian and NF2 tumor cell lines, supporting a PAK1‑centered mechanism outside breast cancer [7]. Other tumor types such as colon, melanoma, leukemia and glioblastoma are repeatedly mentioned as sensitive in preclinical screens, but the precise molecular mediator is not uniformly PAK1 in every report—reviews summarize anticancer activity across cancers while still highlighting PAK1/Akt/mTOR as a recurring axis [8] [6].
3. Wnt/β‑catenin: more linked to migration, EMT and specific resistant breast/colorectal contexts
Evidence that ivermectin inhibits metastasis and epithelial‑to‑mesenchymal transition implicates Wnt/β‑catenin signaling, notably in colorectal models and in endocrine‑resistant breast cancer where Wnt signaling is tied to metastatic gene programs; functional assays show ivermectin reduces migration and invasion through Wnt/β‑catenin/integrin/FAK pathways [4] [5]. Reviews and mechanistic papers therefore position Wnt/β‑catenin as the principal target when the observable effect is reduced motility or EMT rather than autophagic growth arrest [8] [6].
4. Akt/mTOR as both downstream effector and independent target
The Akt/mTOR pathway appears both as a direct downstream consequence of PAK1 inactivation and as a broader node ivermectin influences across tumor types; blockade of Akt/mTOR relieves inhibition of autophagy and contributes to growth suppression in multiple cell lines [2] [7]. Reviews list Akt/mTOR among several pathways ivermectin alters, and in some tumor contexts modulation of Akt/mTOR may be the predominant measurable effect even when PAK1 is not singled out [8] [9].
5. Variation in phenotype: autophagy vs apoptosis vs migration
Ivermectin’s anticancer phenotypes differ across models—cytostatic autophagy via PAK1/Akt/mTOR is emphasized in breast and some ovarian models, caspase‑dependent apoptosis and immunogenic cell death are reported elsewhere, and Wnt‑linked effects dominate migration/metastasis assays—this implies pathway prominence depends on tumor type and the specific assay endpoint researchers measure [8] [7] [4].
6. Caveats, alternative interpretations and research gaps
The literature synthesized here is overwhelmingly preclinical—cell lines and animal models—and reviews call for further mechanistic and translational work to define which tumors and clinical settings might benefit [1] [8]. While multiple papers converge on PAK1→Akt/mTOR in breast cancer, some reviews portray ivermectin as a pleiotropic agent that touches many oncogenic networks (Wnt/TCF, Hippo/YAP1, STAT3), raising the possibility that observed effects reflect network crosstalk rather than a single target [7] [6]. Finally, sources advocating drug repurposing sometimes emphasize breadth of targets as a translational selling point—an implicit agenda that underscores the need for rigorous, tumor‑specific validation [8] [10].