Utilizing TP53 hotspot mutations as effective predictors of gemcitabine treatment outcome in non-small-cell lung cancer

<jats:title>Abstract</jats:title>
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<jats:italic>TP53</jats:italic> mutations are recognized to correlate with a worse prognosis in individuals with non-small cell lung cancer (NSCLC). There exists an immediate necessity to pinpoint selective treatment for patients carrying <jats:italic>TP53</jats:italic> mutations. Potential drugs were identified by comparing drug sensitivity differences, represented by the half-maximal inhibitory concentration (IC50), between <jats:italic>TP53</jats:italic> mutant and wild-type NSCLC cell lines using database analysis. In addition, clinical data from NSCLC patients were collected to evaluate both their <jats:italic>TP53</jats:italic> status and their response to gemcitabine, thereby facilitating further validation. Subsequently, NSCLC cell lines with different <jats:italic>TP53</jats:italic> status (A549 and H1299) were subjected to gemcitabine treatment to investigate the association between <jats:italic>TP53</jats:italic> mutations and gemcitabine response. According to the dataset, NSCLC cell lines carrying <jats:italic>TP53</jats:italic> mutations displayed heightened sensitivity to gemcitabine. From a clinical standpoint, patients exhibiting <jats:italic>TP53</jats:italic> hotspot mutations demonstrated prolonged overall survival upon gemcitabine treatment. In vitro, overexpressing various hotspot <jats:italic>TP53</jats:italic> mutations significantly sensitized H1299 cells to gemcitabine. Moreover, the knockdown of <jats:italic>TP53</jats:italic> in A549 cells notably augmented sensitivity to gemcitabine treatment, as evidenced by cell viability and reproductive cell death assays. Conversely, the overexpression of wild-type <jats:italic>TP53</jats:italic> in H1299 cells led to an increased resistance against gemcitabine. Gemcitabine is a treatment option for patients with non-small cell lung cancer (NSCLC) who carry <jats:italic>TP53</jats:italic> hotspot mutations. This potential effectiveness might arise from its ability to disrupt DNA damage repair processes, leading to G2/M phase cell cycle arrest or an augmentation of mitotic abnormalities, eventually cause cell death. As a result, when planning treatment strategies for NSCLC patients possessing <jats:italic>TP53</jats:italic> hotspot mutations, gemcitabine should be considered to incorporate into the indication.</jats:p>