Exploiting tumor lineage features for precision cancer therapy

Trends in cancer · 2026-01-03

EGFR inhibitor-resistant lung cancers exhibit collateral sensitivity to a covalent, cysteine-independent KEAP1 oligomerizing molecular bridge

Nature Communications · 2026-01-14

Targeted therapies have revolutionized cancer care. Unfortunately, most patients develop refractory, multifocal resistance to these therapies within a matter of months. Here, we demonstrate that the evolution of resistance to EGFR inhibitors in EGFR-mutant non-small cell lung cancer endows cells with hypersensitivity to a PAINS-like small molecule, MCB-613. Systematic proteomic, functional genomic, and biochemical studies revealed that MCB-613 binds KEAP1 in a covalent, cysteine-independent fashion, acting as a divalent molecular bridge that relies upon lysine residues in the KEAP1 dimerization domain to join monomers of KEAP1 together. Oligomerization of KEAP1 by MCB-613 sets into motion a fatal cascade of KEAP1 dysfunction, ROS accumulation, and ATF4/CHOP-dependent cell death. Together, these findings demonstrate that diverse models of EGFR inhibitor-resistant NSCLC share the common feature of elevated integrated stress response activity, and that a covalent molecular bridge which activates non-canonical KEAP1-ATF4 signaling can exploit this feature to select against resistance evolution. EGFR inhibitors are standard of care in patients with EGFR-mutant non-small cell lung cancer (NSCLC) but resistance often develops. Here the authors report that the evolution of EGFR inhibitor resistance in EGFR-mutant NSCLC results in a sensitivity to the compound, MCB-613, and investigate the underlying mechanism of action.

Chromosomal instability and chromosome 17p loss drive convergent <i>NDE1</i> synthetic lethality in metastatic cancer cells

bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-12

Abstract Recent studies have identified recurrent features of metastatic cancer cells such as their increased chromosomal instability (CIN) and frequent loss of the short arm of chromosome 17 (Chr17p). However, it remains unclear whether these features induce synthetic lethal vulnerabilities that can be used to specifically target metastatic disease. Using whole-genome CRISPR/Cas9 loss-of-function screens performed in matched primary and CIN-high brain-metastatic tumor models, we discovered that brain-metastatic cells exhibit increased sensitivity to the loss of diverse regulators of chromosome segregation. Knockout of one such regulator, NDE1, selectively inhibited the growth of brain-metastatic models in vitro and in vivo , an effect driven by the loss of STAG2 and consequent induction of CIN. Surprisingly, dependence on NDE1 was also highly correlated with loss of Chr17p across hundreds of cancer cell lines in DepMap, the result of losing the NDE1 paralog NDEL1 , which resides at this locus. CIN and Chr17p loss are thus independently sufficient to drive NDE1 dependence in brain-metastatic cells, and the presence of both features increases NDE1 dependence additively. These findings demonstrate that metastasis evolution endows cancer cells with specific vulnerabilities, including one that is driven by two recurrently altered molecular features of metastatic disease.

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