immunokinase inhibitor(Angex Pharmaceutical)

Regorafenib is an oral multikinase inhibitor used in later lines for metastatic colorectal carcinoma (mCRC) treatment, but its efficacy and tolerability are low. To improve the response rates and ameliorate adverse effects, different strategies have been implemented. In our study, we examined the effect of statin usage in patients with mCRC treated with regorafenib.

This single-center retrospective study included patients with mCRC who were treated with regorafenib between January 2015 and December 2023. The primary outcomes were progression-free survival (PFS) and overall survival (OS), and the secondary outcomes were adverse effects and the tolerability of regorafenib.

The data of 105 patients were collected retrospectively. The median age of the patients was 66 years, and 60 patients were male. Seventeen patients (16.1%) were receiving statins. Statin-using patients were significantly older than non-users (72 years vs. 66.5 years, p=0.05). Comorbid diseases were more common in patients using statins. The median PFS was 1.9 months for statin users and 4.2 months for statin non-users (p<0.001), and the median OS was 4.7 vs. 6.7 months (p=0.01). Cox regression revealed that statin usage was significantly associated with a higher hazard ratio (HR) for PFS (2.53) and OS (2.06) (both p<0.01 and p=0.02, respectively).

Statins are associated with decreased survival and response rates in patients with mCRC treated with regorafenib. However, further studies are needed to confirm these results.

Ponatinib is a small molecule multi-tyrosine kinase inhibitor clinically approved for anticancer therapy. Molecular mechanisms by which cancer cells develop resistance against ponatinib are currently poorly understood. Likewise, intracellular drug dynamics, as well as potential microenvironmental factors affecting the activity of this compound are unknown. Cell/molecular biological and analytical chemistry methods were applied to investigate uptake kinetics/subcellular distribution, the role of lipid droplets (LDs) and lipoid microenvironment compartments in responsiveness of FGFR1-driven lung cancer cells toward ponatinib. Selection of lung cancer cells for acquired ponatinib resistance resulted in elevated intracellular lipid levels. Uncovering intrinsic ponatinib fluorescence enabled dissection of drug uptake/retention kinetics in vitro as well as in mouse tissue cryosections, and revealed selective drug accumulation in LDs of cancer cells. Pharmacological LD upmodulation or downmodulation indicated that the extent of LD formation and consequent ponatinib incorporation negatively correlated with anticancer drug efficacy. Co-culturing with adipocytes decreased ponatinib levels and fostered survival of cancer cells. Ponatinib-selected cancer cells exhibited increased LD levels and enhanced ponatinib deposition into this organelle. Our findings demonstrate intracellular deposition of the clinically approved anticancer compound ponatinib into LDs. Furthermore, increased LD biogenesis was identified as adaptive cancer cell-defense mechanism via direct drug scavenging. Together, this suggests that LDs represent an underestimated organelle influencing intracellular pharmacokinetics and activity of anticancer tyrosine kinase inhibitors. Targeting LD integrity might constitute a strategy to enhance the activity not only of ponatinib, but also other clinically approved, lipophilic anticancer therapeutics.