Sang Hyun Lee
Duke-NUS Medical School, Singapore
Biography
Achieving robust cancer-specifi c lethality is the ultimate clinical goal. Here we identify a compound with dual-inhibitory properties, named a131 that selectively kills cancer cells, while protecting normal cells. Th rough an unbiased CETSA screen, a proteome-wide drug-target engagement mapping, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological eff ects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally up-regulating PIK3IP1, a suppressor of the PI3K/Akt/ mTOR pathway via altering epigenettic regulation. Strikingly, Ras activation overrides a131-induced PIK3IP1 up-regulation and activates the PI3K/Akt/mTOR pathway. Consequently, Ras-transformed cells override a131-induced growth arrest and enter mitosis where a131’s ability to de-cluster supernumerary centrosomes in cancer cells eliminates Ras-activated cells through mitotic catastrophe. Our discovery of drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a Ras|PIK3IP1|PI3K signaling network in Ras-pathway activated cancer cells and clinical samples from patients with colorectal and lung adenocarcinomas via epigenetic mechanisms.