Getting Around PLX4032: Studies Turn Up Unusual Mechanisms of Resistance to Melanoma Drug

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About half of all melanomas are driven by a mutation in the B-RAF gene, called V600→E. So in 2009, when early small trials showed many patients with the mutation responding to a drug called PLX4032, researchers were jubilant. The drug is now in a pivotal phase III trial for metastatic melanoma; there is talk about accelerated approval; and its developers, Plexxikon and Roche, have already opened an expanded access program.

The only bad news about PLX4032 so far is the duration of response: Patients are developing resistance to the small-molecule inhibitor in 2–18 months. Phase II trial results, announced in November, showed that 52% of patients with the mutation responded to PLX4032, but the median duration of response was 6.2 months.

Now, two research groups exploring this acquired resistance report that melanoma tumors use multiple distinct routes to get around PLX4032. The drug works by inhibiting the mutated B-RAF, which otherwise drives tumor growth by activating the mitogen-activated protein (MAP) kinase pathway. Acquired resistance, however, does not seem to be secondary mutations in the B-RAF target gene itself. Rather, the melanoma tumors and cell lines analyzed to date use other kinase proteins to sidestep B-RAF and reactivate the pathway. Or they compensate for the loss of MAP kinase pathway activity by upregulating other, unrelated growth factor receptor pathways.