ASPM Induces Radiotherapy Resistance by Disrupting Microtubule Stability Leading to Chromosome Malsegregation in Non‐Small Cell Lung Cancer

Radiotherapy (RT) resistance remains a substantial challenge in cancer therapy. Although physical factors are optimizing, the biological mechanisms for RT resistance are still elusive. Herein, we explored potential reasons for this difficult problem by generating RT-resistant models for in vitro and in vivo experiments. We found that abnormal spindle-like microcephaly-associated protein (ASPM) was highly expressed in RT-resistant samples and significantly correlated with disease advance in lung adenocarcinoma. Mechanistically, ASPM helps RT-resistant cells to evade spindle checkpoint surveillance and complete cell division after irradiation through destruction of microtubule stability, with subsequent increases in chromosome mis-segregation and deteriorating chromosomal stability during mitosis. Depletion of ASPM stabilized microtubules and significantly decreased chromosome mis-segregation, restoring the sensitivity of RT-resistant cells to radiation. We further found, with bioinformatics analysis, amino acid sequence 963-1263 of ASPM as a potential new drug target for overcoming RT resistance and identified 9 drug pockets within this domain for clinical translation. Our findings suggest that ASPM is a key regulator with an important role in promoting RT resistance in non-small cell lung cancer, and that suppressing or blocking its expression could be worth exploring as therapy for a variety of RT-resistant cancers.