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G2-arrested B lymphoma is prone to Wee1 inhibition
treatment, which concomitantly occurred with acquired sensitivity to Wee1 inhibitor. We propose that the plastic- ity of G2 phase-arrest could be exploited for the design of personalized B-cell lymphoma therapy: (i) the cell cycle arrest pattern could be determined upon treatment with different chemotherapeutic agents for each individual patient; (ii) G2 phase-arrest inducing agents could be identified, which could then be combined with Wee1 inhibitor to achieve more effective treatment for the cor- responding patient.
Combined treatment with Wee1 inhibitor and Ara-C has been tested for acute myeloid leukemia and T-cell acute lymphocytic leukemia,14,15 and Wee1 inhibition was also tested in different types of cancers including medulloblas- toma and hepatocellular carcinoma;42-45 however, the underlying mechanisms remain incompletely understood. Mitotic entry is restricted by the phosphorylation of CDK1, and inhibition of pCDK1 could abrogate the G2/M checkpoint and propel G2-phase cells to enter the M phase.44,46,47 This premature M phase entry would elicit mitotic catastrophe or apoptosis, which has been suggest- ed to act as an effective means of killing cancer cells.9,13 Previous studies found that Wee1 inhibition promoted G1 or S phase-arrested cells to undergo premature mitotic
entry.16,48 However, our data suggest that only G2 phase- arrested B cell lymphomas were sensitive to combined treatment with Wee1 inhibitor and Ara-C or doxorubicin. In line with in vitro data, our in vivo transplant G1XP model demonstrated a potential of combined Ara-C and Wee1 inhibitor treatment in eradicating B-cell lymphomas. Prior studies showed that Ara-C treatment activated Chk1,49 and Chk1 inhibitors synergize with Ara-C in suppressing acute myeloid leukemia.49,50 Consistently, we found that Ara-C treatment activated Chk1 and Chk2 in most of the B-cell lymphoma lines examined. Overall, these data suggest that cell cycle modulators may enhance the sensitivity of cancer cells to chemotherapeutic agents (e.g., Ara-C or doxoru- bicin), and that the combinatorial therapy may be more effective. Of note, we observed that a small percentage of recipients died early in the Ara-C/MK1775 group in the absence of lymphoma recurrence, suggesting that the toxic effects of combined Ara-C/MK1775 treatment need to be tested in future studies.
Acknowledgments
We thank Michael Rice, Stephanie Cung, and Brittany C. Waschke for their technical help. We apologize to those whose work is not cited here due to length restrictions.
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