Overall, we provided the evidence that increased levels of Shh could be related to the emergence of TKI resistance, providing the rationale to implement larger studies in EGFR-mutated NSCLC treated with TKIs, with the following aims: to validate plasma levels of Shh as a new criterion of patient stratification, and to use and to validate the efficacy of Hh inhibitors in clinical studies. Here, EGFR is linked to non-small cell lung carcinoma.