Emergence and Targeting of Acquired and Hereditary Resistance to Multikinase RET Inhibition in Patients With RET-Altered Cancer.

The RET receptor tyrosine kinase is oncogenically activated by I RET i gene fusions in 1% to 2% of non-small-cell lung cancers (NSCLC) and by I RET i gene mutations in most medullary thyroid cancers (MTC).[1] Although multikinase inhibitors (MKIs) with nonspecific anti-RET activity are approved for the treatment of MTC irrespective of I RET i mutation status, their investigational use for patients with I RET i fusion-positive NSCLC has been limited by substantial off-target adverse effects that lead to dose reductions and inadequate RET-specific inhibition.[2]-[7] As a result, tumor responses to MKIs have been infrequent and short lived, and a comprehensive molecular understanding of MKI response and resistance is lacking. It is highly potent against and selective for diverse founder activating RET alterations in human cancers, and in preclinical experiments, it overcomes RET V804 gatekeeper mutations, which have been identified in rare patients with acquired resistance to anti-RET MKIs. To our knowledge, case 1 is the second patient with NSCLC to be described as having an acquired RET gatekeeper mutation after prior anti-RET MKI treatment and the first to be treated successfully with RET-targeted therapy.[14] To our knowledge, this is also the first published report of a patient with hereditary RET V804M-mutant MTC treated successfully with RET-targeted therapy. [Extracted from the article]