CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation.

Inhibition of checkpoint kinase 1 (CHK1) is a promising therapeutic strategy to increase the effectiveness of DNA-damaging drugs in pancreatic cancer. However, owing to the multiple roles of CHK1 in the DNA damage response (DDR) pathway, the molecular mechanism of chemosensitization by CHK1 inhibitors is not definitive. In the present study, we explored the antitumor mechanism of LY2603618, a specific CHK1 inhibitor, alone or in combination with gemcitabine in 5 pancreatic cancer cell lines. LY2603618 treatment of the pancreatic cancer cell lines resulted in growth inhibition, with IC50 values ranging from 0.89 to 2.75 µM, but limited cell death. Importantly, treatment of pancreatic cancer cell lines with LY2603618 reduced the levels of pCDC25C, pCDK1, and pCDK2, accompanied by DNA damage and RRM1/2 downregulation. Furthermore, LY2603618 synergized with gemcitabine treatment to induce growth inhibition and apoptosis in pancreatic cancer cells. Mechanistic investigations showed that gemcitabine sensitization by CHK1 inhibition was associated with CDK­dependent RRM1/2 downregulation and DNA damage enhancement. These findings provide a basis for further development of combining CHK1 inhibitors and gemcitabine to treat pancreatic cancer.

Cucurbitacin B and SCH772984 exhibit synergistic anti-pancreatic cancer activities by suppressing EGFR, PI3K/Akt/mTOR, STAT3 and ERK signaling.

Cucurbitacin B (CuB) is a natural tetracyclic triterpene product and displays antitumor activity across a wide array of cancers. In this study, we explored the anti-pancreatic cancer activity of CuB alone and in combination with SCH772984, an ERK inhibitor, in vitro and in vivo. CuB inhibited proliferation of pancreatic cancer cells by arresting them in the G2/M cell cycle phase. This was associated with inhibition of EGFR expression and activity and downstream signaling, including PI3K/Akt/mTOR and STAT3. Interestingly, ERK activity was markedly enhanced by activating AMPK signaling after 12 h of CuB treatment. SCH772984 potentiates the cytotoxic effect of CuB on pancreatic cancer cells through complementary inhibition of EGFR, PI3K/Akt/mTOR, STAT3 and ERK signaling, followed by an increase in the pro-apoptotic protein Bim and a decrease in the anti-apoptotic proteins Mcl-1, Bcl-2, Bcl-xl and survivin. Furthermore, combined therapy with CuB and SCH772984 resulted in highly significant growth inhibition of pancreatic cancer xenografts. These results may provide a basis for further development of combining CuB and ERK inhibitors to treat pancreatic cancer.