Researchers Identify Survival Pathway Undermining Targeted Cancer Drugs

Image: Many targeted tumors activate a backup pathway to sustain growth when tyrosine kinase—shown here as strands—is inhibited (Photo courtesy of Massachusetts Institute of Technology)

Massachusetts Institute of Technology (Cambridge, MA, USA) researchers mapped signaling programs with phosphoproteomics before and after inhibitor exposure in lung cancer models. The analyses showed that, even when drugs silenced their intended targets, an alternative network driven by SRC family kinases was already active in nonresponding cells. That network supports proliferation and may facilitate migration, providing a cell‑intrinsic route to persistence despite therapy.

The team evaluated six patient‑derived lung cancer cell lines, two each harboring EGFR, MET, or ALK alterations, arranged as sensitive–resistant pairs to the corresponding tyrosine kinase inhibitor. Phosphoproteomics identified phosphorylation changes across pathways and confirmed on‑target blockade in all lines, including resistant ones. However, resistant models maintained survival via pre‑existing SRC‑regulated signaling. Treating those cells with both a tyrosine kinase inhibitor and an SRC inhibitor produced substantially higher cell‑death rates, and a clinical trial combining the tyrosine kinase inhibitor osmertinib with an SRC inhibitor is underway in patients with lung cancer.

The study, published in PNAS on March 25, 2026, also demonstrated feasibility of using phosphoproteomics on patient biopsy samples to detect tumors with SRC pathways already engaged. Similar SRC activation has been observed by the group in melanoma and glioblastoma, suggesting a broader relevance across malignancies described in the report. The findings may also account for some tumor recurrences after initial response to tyrosine kinase inhibition, when cells later activate the same survival pathway.

"We are really excited to watch these clinical trials and to see how well patients do on these combinations. And I really think there's a future for using tyrosine phosphoproteomics to guide this clinical decision-making," said Forest White, the Ned C. and Janet C. Rice Professor of Biological Engineering at MIT.

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