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Preprint WatchModerateSeptember 17th, 2026

CDK4 or CDK6 upregulation induces DNA replication stress and genomic instability to cause EGFR targeted therapy resistance in lung cancer

Gini, B.; Gui, P.; Wu, W.; Kerr, D. L.; Tan, L.; Barbosa, D.; Olivas, V.; Allegakoen, P.; Gomez, C.; Halliday, P.; Elmes, S.; Steri, V.; Chakrabarti, T.; Bivona, T. G.; Blakely, C. M.

CDK4 or CDK6 upregulation limits EGFR inhibitor-induced proliferative arrest and drives replication stress, TPX2 elevation, ATM activation and genomic instability, positioning CDK4/6 amplification as a mechanism of acquired EGFR tyrosine kinase inhibitor resistance.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This revision argues that CDK4 or CDK6 amplification causes EGFR inhibitor resistance in lung adenocarcinoma through replication stress and genomic instability rather than through EGFR pathway reactivation. Both EGFR entries in the Claidex graph sit in the same population and were stopped before any resistance question could be addressed. The radioconjugate program failed on target uptake and dosimetry rather than on tumour biology (fpi-2107-egfr-cmet-nsclc-dosimetry-uptake-failure), and the chimeric degrader program was shut down for sponsor reasons at Phase 1 (bg-60366-egfr-cdac-nsclc-strategic-shutdown). The practical reading is that next-generation EGFR-directed modalities entering this indication should measure CDK4 and CDK6 copy number at baseline, because a resistance mechanism that operates downstream of EGFR occupancy will not be visible in a target engagement or degradation readout.

Abstract excerpt

Epidermal growth factor receptor (EGFR) mutant lung adenocarcinomas (LUAD) harbor a complex landscape of genetic co-alterations and potential oncogenic interactions. Among them are recurrent amplifications of the cell cycle regulatory genes CDK4 and CDK6, which have been clinically implicated in resistance to EGFR tyrosine kinase inhibitors (TKIs). However, the mechanisms by which CDK4/6 upregulation promotes therapy resistance remain poorly defined. Here, we demonstrate that CDK4 or CDK6 overexpression limits EGFR inhibitor-induced proliferative arrest, promoting continued cell cycle progression. This is accompanied by elevated replication stress, increased TPX2 expression, DNA damage leading to ATM activation, and ultimately genomic instability. Integrative transcriptomic and copy number analyses of EGFR-mutant LUAD tumors from both patients and preclinical models revealed that CDK4 or CDK6 amplification is associated with the upregulation of genes linked to tumor progression, including AGR2, ASNS, and STEAP1. CDK4 amplification was also highly correlated with gene expression changes associated with epithelial-to-mesenchymal transition (EMT) in a single-cell RNA sequencing dataset from patient biopsies. In preclinical models, co-treatment with CDK4/6 and EGFR inhibitors restored proliferative arrest, induced tumor cell apoptosis, and reduced replication stress, DNA damage, an

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.