Cancers are frequently driven by the hyperactive signaling of tyrosine kinases, and many targeted cancer therapies have been developed over the past quarter century that inhibit their activity. Although many of these drugs have benefited patients, tumors frequently resist their effects despite being driven by the kinases they target. A study by former Ludwig MIT Graduate Fellow Cameron Flower—now a postdoc in Franziska Michor’s lab at Ludwig Harvard and in Leonard Zon’s lab at Boston Children’s Hospital—and his former advisor Forest White used phosphotyrosine immunoaffinity enrichment and high-sensitivity mass spectrometry on cancer cell lines to identify signaling networks that drive sensitivity or tolerance to tyrosine kinase inhibitors (TKIs). The pair quantified endogenous levels of 1,222 phosphotyrosine sites across the proteomes of tyrosine kinase-driven human cancer cell lines that show variable response to genotype-matched TKIs. They found that TKIs are equally effective at inhibiting tyrosine kinase activity in both TKI-sensitive and insensitive cells but that more robust phosphotyrosine signaling was associated with reduced sensitivity to TKIs. They reported in a March issue of PNAS that cells that tolerate a variety of TKIs share high activity of the SRC/ABL family of kinases, which may be a general survival pathway conferring intrinsic resistance to therapy. A number of clinical trials now underway co-target signaling by SRC/ABL family kinases, offering a fortuitous clinical test of their hypothesis.
Tyrosine phosphoproteome profiling identifies cell-intrinsic signals limiting the efficacy of tyrosine kinase inhibitor therapies
PNAS 2026 March 25