July 2026: Publication in Cell Death & Differentiation
Hitting two survival switches at once kills lung cancer cells within hours
Non-small cell lung cancer (NSCLC) is notoriously hard to kill: the cells survive chemotherapy because proteins of the BCL-2 family keep their built-in self-destruct programme, apoptosis, switched off. Liyang Wu and colleagues from the group of Thomas Kaufmann screened ten human NSCLC cell lines with drugs that block these survival proteins one at a time — and found that blocking any single one has little effect. Blocking two of them together, BCL-XL and MCL-1, was a different story: most of the cell lines committed to apoptosis within a few hours, and the effect was irreversible, independent of the frequently mutated tumour suppressor p53, and strictly dependent on the mitochondrial cell death machinery. Cell lines that initially looked resistant were in fact simply not fully hit, and died once BCL-XL was blocked more effectively or removed altogether using the PROTAC degrader DT2216 — a platelet-sparing approach that addresses the main side effect that has held BCL-XL inhibitors back in the clinic. Together, the study reframes apoptosis resistance in NSCLC as a joint effort of two proteins rather than a dependency on one, and points to a fast, potentially exploitable therapeutic vulnerability. Figure from Wu et al., Cell Death & Differentiation 2026 shows: one week after treatment: lung cancer cells survive each drug on its own (dishes 2+3, purple colonies), but combined inhibition of BCL-XL (A-1331852) and MCL-1 (S63845) leaves no survivors.
