Table 1.

Unsuccessful studies in targeting KRAS in pancreatic cancer

Agent	Rationale	Mechanism of resistance	Reference
Farnesyl transferase inhibitors (FTIs)	Prevention of KRAS plasma membrane localization	Alternative prenylation by geranyl geranyl transferases, which allows KRAS localization at the plasma membrane	[68–70]
RAF inhibitors (e.g., vemurafenib)	Inhibition of KRAS mediated RAF activation and downstream signaling	RAF inhibitors bound to wild type RAF in KRAS mutant cells, resulted in the formation of RAF dimers that activated downstream signaling	[77–80]
mTOR inhibitors (e.g., everolimus)	Inhibition of PI3K pathway downstream of KRAS	Activation of alternative downstream pathways; Paradoxical AKT phosphorylation and cyclin D1 activation leading to increased proliferation.	[85, 86]