Figure 2. Acquired resistance mechanisms to CDK4/6 targeting.

Multiple resistance mechanisms have been identified and validated in human patient samples. These include two separate NRAS mutations (Q61H/L) identified in a mutant BRAF melanoma patient and a PI3KCA E545K mutation found in a mutant NRAS melanoma patient. PDK1 expression was also increased in post-palbociclib treated breast cancer patient samples compared to naïve tumors. In a mouse xenograft model, NRAS amplification mediated MEK inhibitor plus CDK4/6 inhibitor resistance. Together, these resistance mechanisms led to upregulation of mTOR-S6 pathway and provided a therapeutic window for mTOR/S6K targeting. In pre-clinical studies, other alterations were identified within cell cycle components, such as CDK6 and cyclin E amplification. Next generation CDK inhibitors are currently in development to concurrently target CDK2 to combat resistance.