KRAS is one of the deadliest oncogenes in cancer, contributing to 98% of pancreatic, 45% of colon and 31% of lung tumors. Traditional strategies have heavily focused on inhibiting its enzymatic activities. However, such strategies have been very challenging. So far two inhibitors targeting a minor G12C mutation of KRAS have been approved by the FDA to treat non-small cell lung cancer. Latest clinical data show confusing results, potentially inflicting more harm to patients. Patients who initially respond positively to these drugs also quickly relapse by developing resistance against these inhibitors. We, thus, need to continue to explore alternative strategies. A hallmark of KRAS-dependent cancer is that KRAS mutants, despite being constantly active, must congregate in signaling nanoclusters on the cell surface. They stop functioning when mislocalized from the cell surface. We first reported that a key structural building block of KRAS cancer nanoclusters is a type of lipids, called phosphatidylserine (PS) lipids with unsaturated fatty acid tails. Thus, it is possible that changing structures of PS tails may attenuate stability of KRAS nanoclusters and consequentially compromise KRAS cancer signaling. A major advantage of this strategy is that all KRAS cancer mutants share similar unsaturated PS lipids. Thus, changing synthesis of unsaturated PS lipids may simultaneously inhibit all KRAS mutants. A major concern is that many other normal cell function may also depend on the unsaturated PS lipids. Thus, this approach may affect normal cell function and inflict high toxicity. We focus significant effort to systematically examine this approach. Specifically, lysophosphatidycholine acyltransferase 3 (LPCAT3) is a main enzyme catalyzing the generation of polyunsaturated lipids. We recently discovered that inhibition of LPCAT3 depletes polyunsaturated PS, disrupts the cancer nanoclusters of KRAS mutants, inhibits KRAS-mediated cancer signaling and suppresses cancer activities of KRAS-driven human pancreatic ductal adenocarcinoma (PDAC) cells. More excitingly, we found that inhibiting LPCAT3 has no effect on wild-type KRAS-expressing cells tested, strongly suggesting that LPCAT3 inhibitors do not affect normal cell function and have low toxicity. We also show that inhibiting LPCAT3 suppresses human PDAC lines expressing different KRAS mutants, suggesting that LPCAT3 can be a novel target for broad-spectrum inhibition of multiple KRAS mutants. Since tumors acquire resistance in part by generating secondary mutations of KRAS, LPCAT3 inhibition may re-sensitize resistant tumors. So far, our findings in cell cultures are very encouraging. Here, we propose to obtain crucial animal model data, mainly human tumors formed in live mice. These important animal data will allow us to validate that our novel approach is viable and may be applied in the clinic in the future.