= Solution
Two distinct possibilities are \b[a second <mutation> affecting drug sensitivity of the targeted <receptor tyrosine kinase>], so that it remains active at the achieved inhibitor concentration, and \b[activation of a bypass signaling route], such as another <receptor tyrosine kinase> or a downstream <Ras> or <protein kinase> component, restoring proliferation despite inhibition of the original target. The resistant population may arise by selection of rare pre-existing <biological cells> or by later acquisition of a change; recurrence alone cannot distinguish those histories. Compare target engagement, target <phosphorylation> and downstream signaling in the original and recurrent samples, with <DNA sequencing> and functional rescue or perturbation of the candidate resistance mechanism.
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