N. Mohana-Kumaran , K.M. Lucas , W. Weninger ,, , J.D. Allen , N.K. Haass
Introduction: Drug resistance in melanoma is commonly attributed to ineffective apoptosis pathways. Inhibiting anti-apoptotic BCL-2 and its relatives is an attractive strategy for sensitizing lymphoid malignancies to drugs but it has been largely unsuccessful for melanoma and other solid tumors. ABT-737, a small-molecule BH3-mimetic, selectively inhibits BCL-2, BCL-XL and BCL-w and shows promise for treating leukemia, lymphoma and small cell lung cancer. Melanoma cells are insensitive to ABT-737 but MCL-1 inhibition reportedly increases the sensitivity of other tumors to the compound.
Method: The efﬁ cacy of MCL-1 and BFL-1 inhibition for sensitizing melanoma cells to ABT-737 was investigated by shRNA-mediated knockdown or overexpression of their antagonist NOXA in two-dimensional cell culture, a threedimensional organotypic spheroid model, and an in vivo model.
Results: MCL-1 downregulation or NOXA overexpression strongly sensitized melanoma cells to ABT-737 in vitro. NOXA-inducing cytotoxic drugs also strongly sensitized melanomas to ABT-737 although, surprisingly, not vice versa. The drugs most suitable are not necessarily those normally used to treat melanoma. Resistance to ABT-737 occurred quickly in 3D melanoma spheroids through reduced NOXA expression although experiments with both xenografts and 3D spheroids suggest that penetration of ABT-737 into tumor masses may be the principal limitation, which may be obviated through use of more diffusible BH3-mimetics.
Conclusion: Sensitization of tumors to BH3-mimetics by cytotoxic drugs that induce NOXA is a therapeutic strategy worth exploring for the treatment of melanoma and other solid cancers.