IC Regimen: Delaying Resistance to Lorlatinib in ALK Driven Cancers by Adding Repurposed Itraconazole and Cilostazol
Open accessAbstract
Lorlatinib is a pharmaceutical ALK kinase inhibitor used to treat ALK driven non-small cell lung cancers. This paper analyses the intersection of past published data on the physiological consequences of two unrelated drugs from general medical practice—itraconazole and cilostazol—with the pathophysiology of ALK positive non-small cell lung cancer. A conclusion from that data analysis is that adding itraconazole and cilostazol may make lorlatinib more effective. Itraconazole, although marketed worldwide as a generic antifungal drug, also inhibits Hedgehog signaling, Wnt signaling, hepatic CYP3A4, and the p-gp efflux pump. Cilostazol, marketed worldwide as a generic thrombosis preventative drug, acts by inhibiting phosphodiesterase 3, and, by so doing, lowers platelets’ adhesion, thereby partially depriving malignant cells of the many tumor trophic growth factors supplied by platelets. Itraconazole may enhance lorlatinib effectiveness by (i) reducing or stopping a Hedgehog-ALK amplifying feedback loop, by (ii) increasing lorlatinib’s brain levels by p-gp inhibition, and by (iii) inhibiting growth drive from Wnt signaling. Cilostazol, surprisingly, carries minimal bleeding risk, lower than that of aspirin. Risk/benefit assessment of the combination of metastatic ALK positive lung cancer being a low-survival disease with the predicted safety of itraconazole-cilostazol augmentation of lorlatinib favors a trial of this drug trio in ALK positive lung cancer.
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Cilostazol, a phosphodiesterase-3 inhibitor, may reduce platelet-mediated tumor support by decreasing platelet aggregation and growth factor release.
“Cilostazol, a phosphodiesterase-3 inhibitor, may reduce platelet-mediated tumor support by decreasing platelet aggregation and growth factor release.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [55]
Itraconazole inhibits P-glycoprotein, CYP3A4, Wnt signaling, and hedgehog signaling, potentially increasing lorlatinib brain penetration and disrupting tumor growth signaling in ALK-positive non-small cell lung cancer.
“ITZ inhibits P-glycoprotein (P-gp), CYP3A4, Wnt signaling, and hedgehog signaling, potentially increasing lorlatinib brain penetration and disrupting tumor growth signaling.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [55]
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Salgado, M. Á. V., Barco, S. D., Sepúlveda-Sánchez, J. M., Alonso, M. D., Pineda, E., Balañá, C., Martinez‐García, M., & Gironés, R. (2025) · Nature Communications · doi:10.1038/s41467-025-66747-z · Cited by 4 · see citing works
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Self-citation
- Authors
- Kast, R. E.
- Affiliations
- IIAIGC Study Center, Burlington, VT 05408, USA
- Corresponding author
- Kast, Richard E.
- ORCID
- Kast, Richard E.
- Venue
- Cells
- Publisher
- MDPI AG
- Published
- 2024-07-10
- Volume
- 13
- Issue
- 14
- Pages
- 1175
- ISSN
- 2073-4409 (ISSN-L)
- PMC
- PMC11274432
- OpenAlex
- W4400486430
- Cited by
- 4
- References
- 172
- Citations by year
- 2026: 2 · 2025: 2
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cells (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- lorlatinib, ALK-positive non-small cell lung cancer, itraconazole, cilostazol, drug repurposing, drug resistance, Hedgehog signaling, Wnt signaling, CYP3A4 inhibition, P-glycoprotein inhibition, phosphodiesterase 3 inhibition, platelet adhesion, combination therapy, brain penetration
- MeSH terms
- Cilostazol, Anaplastic Lymphoma Kinase, Aminopyridines, Carcinoma, Non-Small-Cell Lung, Humans, Lactams, Lung Neoplasms, Pyrazoles, Itraconazole, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, Drug Repositioning
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