(From the January 2014 issue of Research Now)
Certain types of childhood cancers, such as low-grade brain tumors, may develop resistance to an anti-cancer drug called selumetinib, which inhibits MEK and BRAF signaling—both necessary for cancer growth. In research published in October in Clinical Cancer Research, Hemant Bid, PhD, post-doctoral scientist in Dr. Peter Houghton’s lab at the Center for Childhood Cancer and Blood Diseases, and colleagues found that resistant tumors may respond to selumetinib treatment when it is combined with LLL12, a treatment that inhibits a pathway called STAT3.
BRAF signaling appears to be responsible for childhood astrocytoma tumor growth and spread. Selumetinib is a drug that—in most tumors—inhibits the MEK pathway, preventing the BRAF signaling from continuing cancer cell growth and proliferation. Some of the tumors typically targeted with selumetinib, however, develop resistance to the drug and appear unaffected by MEK inhibition.
The team discovered that when selumetinib was used to treat resistant tumors, a pathway called STAT3 was activated. An overabundance of STAT3 signaling enabled the tumors to overcome the MEK inhibition to keep producing new cancer cells.
The researchers tried treating these resistant tumors with LLL12, a therapy that inhibits the STAT3 pathway. Although LLL12 treatment by itself did not affect the tumors, when they combined LLL12 with selumetinib, the tumors responded to treatment as if no resistance existed.
The results suggest that combined treatment may help address these resistant childhood brain tumors and may even help slow or prevent the onset of resistance in susceptible tumors.
Hemant Bid is a postdoctoral scientist in Houghton’s Lab.
Bid HK, Kibler A, Phelps D, Manap S, Xiao L, Lin J, Capper D, Oswald D, Geier B, Dewire M, Smith PD, Kurmasheva RT, Mo X, Fernandez S, Houghton PJ. Development, Characterization, and Reversal of Acquired Resistance to the MEK1 Inhibitor Selumetinib (AZD6244) in an In Vivo Model of Childhood Astrocytoma.Clinical Cancer Research. 2013 Oct 16. [Epub ahead of print] Impact Factor: 7.89