SPP1 overexpression is linked to unfavorable outcomes in patients with ALK/TP53 co-mutated lung cancer

Patients with ALK/TP53 co-mutated lung cancer experience notably worse progression-free survival (PFS) and overall survival (OS) than those with TP53 wildtype. Nevertheless, the precise molecular mechanism underlying poor survival of patients with ALK/TP53 co-mutated lung cancer is unclear. In the cohort of 77 patients with ALK -rearranged lung cancer, TP53 mutations were identified in fifteen cases (19.5%). Compared to patients with TP53 wildtype, patients with ALK/TP53 co-mutated lung cancer experienced a significantly shorter median OS (48 months vs. 58 months, P = 0.0454). This difference was confirmed in ALK inhibitor plus chemotherapy subgroup. Median OS was 27 months for patients with TP53 mutated lung cancer, compared to 62 months for those with TP53 wildtype ( P = 0.0011). Furthermore, a significant upregulation of ALK, MET, GRB7, and SPP1 mRNA expression was identified in ALK -rearranged lung cancer tissues compared with paired non-tumor tissues via NanoString assay. The mRNA level of SPP1 was notably higher in ALK/TP53 co-mutated cases than TP53 wildtype cancer. Overexpression of SPP1 and PD-L1 proteins in ALK/TP53 co-mutated lung cancer was verified through immunohistochemistry (IHC) in contrast to paired non-tumor tissues and TP53 wildtype cases. Finally, hypomethylation of the SPP1 promoter region was detected using targeted bisulfite sequencing. Thus, SPP1 overexpression is linked to unfavorable outcomes in patients with ALK/TP53 co-mutated lung cancer, and promoter hypomethylation of SPP1 has been likely associated with its aberrant overexpression. SPP1 may become the key prognostic biomarker and the promising molecular target for treating ALK -rearranged lung cancer.