Constitutive EGFR activation induced by PTPRR downregulation confers resistance to KRAS inhibitors

KRASG12C inhibitors, such as sotorasib, show clinical efficacy for non-small cell lung cancer (NSCLC) positive for the G12C mutations of KRAS, but primary and acquired resistance to these drugs remains a clinical problem. We here show that development of resistance to sotorasib in KRASG12C-positive NSCLC cells was mediated by constitutive activation of EGFR resulting from downregulation of the protein tyrosine phosphatase receptor type R (PTPRR). PTPRR has been identified as a physiological regulator of ERK signaling in several cancer types. In our study, PTPRR was demonstrated to bind directly to EGFR, facilitating its dephosphorylation on tyrosine residues. Resumption of PTPRR expression in the resistant cells attenuated EGFR phosphorylation and restored sotorasib sensitivity. PTPRR downregulation was associated with gene promoter hypermethylation in the sotorasib-resistant cells and NSCLC tissue samples. Furthermore, low PTPRR expression in tumor specimens was associated with shorter progression-free and overall survival for NSCLC patients treated with sotorasib. In contrast to sotorasib, high PTPRR expression was associated with the poor response to EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC, suggesting that PTPRR may broadly regulate EGFR dependence in NSCLC. Finally, dual blockade of KRASG12C and EGFR showed a substantial antitumor effect in a xenograft model of sotorasib-resistant NSCLC. This approach is therefore a rational therapeutic strategy for KRASG12C-positive NSCLC, especially for tumors showing PTPRR downregulation.