The invention relates to methods for preventing or treating resistance to EGFR inhibitors in cancer patients. More particularly, after performing a screen for small molecules potentially capable of countering cancer resistance to EGFR TKI, inventors identified the multikinase inhibitor sorafenib, which has the property, in combination with EGFR TKI, to prevent the enrichment of tumor cells containing mutations responsible for NSCLC resistance to first and third generation EGFR TKI. These data indicate that this multikinase inhibitor can prevent resistance to several generations of EGFR TKI. These in vitro data were confirmed in an in vivo xenograft mouse model of NSCLC. Finally these data were reproduced in cancer cells using SC-1, a sorafenib analogue. Accordingly, the invention relates to a method of preventing and/or treating cancer resistance to treatment with an epidermal growth factor receptor (EGFR) inhibitor in a subject in need thereof comprising administering to the subject sorafenib drug or sorafenib analogue, alone or in combination with an EGFR inhibitor.
