Statin-dye conjugates for selective targeting of KRAS mutant cancer cells

Over 90% of pancreatic ductal adenocarcinoma (PDAC) patients involve KRAS mutations (KRAS ^MUT), for which current treatment options are limited. Statins, commonly used to lower cholesterol, have demonstrated certain selective toxicity towards KRAS-transformed cells, prompting the question of whether statins could achieve selective uptake specifically in KRAS ^MUT cells. To investigate this, we synthesized statin-dye conjugates by attaching a fluorescent dye (Cy5.5) to two statins: simvastatin and pravastatin, aiming to assess whether selective uptake indeed occurs. Our findings revealed that these conjugates exhibited markedly enhanced uptake in KRAS ^MUT cells compared to KRAS wild-type (KRAS ^WT) cells. Given the magnitude of the selective uptake, we realized that the uptake of these conjugates itself is of considerable intrinsic interests. We evaluated the uptake of these conjugates in both KRAS ^MUT and KRAS ^WT cells and examined their potential to selectively target KRAS ^MUT pancreatic cancer cells (PCCs) using an engineered PDAC tumor model co-cultured with PCCs and cancer-associated fibroblasts (CAFs). Our findings indicate that KRAS ^MUT cancer cells exhibited higher uptake of statin-Cy5.5 conjugates via enhanced macropinocytosis compared to KRAS ^WT cancer cells and CAFs. We also found enhanced uptake of the statin-Cy5.5 conjugate in MCF10A cells with PTEN deficiency, a condition known to elevate macropinocytosis, compared to control MCF10A cells with wild-type PTEN. Notably, in the PCC and CAF co-culture model, the pravastatin-Cy5.5 conjugate selectively killed KRAS ^MUT PCCs without affecting the KRAS ^WT CAFs. These findings highlight the potential of stain-drug conjugates as targeted delivery vehicles for KRAS ^MUT cancer therapy.