CDKN2A Deletion Confers Resistance to MEK inhibition in Pancreatic Cancer

OBJECTIVEIdentifying markers of drug resistance is paramount to the goal of personalized cancer therapy. Here, we identify CDKN2A deletion as a potential marker for resistance to MEK inhibition in pancreatic... [ view full abstract ]

OBJECTIVE

Identifying markers of drug resistance is paramount to the goal of personalized cancer therapy. Here, we identify CDKN2A deletion as a potential marker for resistance to MEK inhibition in pancreatic cancer.

METHODS

Panc-1 (KRAS^G12D;CDKN2A^del) and MiaPaca-2 (KRAS^G12C; CDKN2A^del) human pancreatic cancer cells were transplanted into the flanks of immunodeficient mice, which were treated with binimetinib (MEK inhibitor), ribociclib (CDK4/6 inhibitor), or combination for 28 days. Tumor growth was monitored regularly. Similarly, PC-13 (KRAS^Q61H; CDKN2A^wt) and PC-17 (KRAS^G12D; CDKN2A^wt) human pancreatic tumor xenografts grown in the flanks of immunodeficient mice were treated with MEK inhibitor, CDK4/6 inhibitor, or combination for 28 days and monitored for tumor growth. At the end of treatment, histologic analysis for proliferation, apoptosis, and stromal content was performed and tumor lysates were subjected to Western blot analysis of relevant signal transduction pathways.

RESULTS

Both CDKN2A mutant xenografts exhibited resistance to MEK inhibition, achieving only 40% response for Panc-1 and 50% for MiaPaCa-2. This was enhanced by the addition of CDK4/6 inhibitor, to 94% for Panc-1 and 75% for MiaPaca-2. Both CDKN2A wildtype xenografts exhibited sensitivity to MEK inhibition, achieving 91% response for PC-13 and 88% for PC-17. Therapeutic response was not significantly enhanced by the addition of CDK4/6 inhibitor.

CONCLUSION

We demonstrated a significantly different therapeutic response to MEK inhibition in pancreatic cancer based on the mutational status of CDKN2A, suggesting that CDKN2A deletion may confer resistance to MEK inhibition and warrant treatment with CDK4 inhibitors.