Overcoming cancer drug-resistance calls for novel strategies targeting abnormal alternative splicing

Abnormal gene alternative splicing (AS) events are strongly associated with cancer progression. Here, we summarize AS events that contribute to the development of drug resistance and classify them into three categories: alternative cis-splicing (ACS), alternative trans-splicing (ATS), and alternative back-splicing (ABS). The regulatory mechanisms underlying AS processes through cis-acting regulatory elements and trans-acting factors are comprehensively described, and the distinct functions of spliced variants, including linear spliced variants derived from ACS, chimeric spliced variants arising from ATS, and circRNAs generated through ABS, are discussed. The identification of dysregulated spliced variants, which contribute to drug resistance and hinder effective cancer treatment, suggests that abnormal AS processes may together serve as a precise regulatory mechanism enabling drug-resistant cancer cell survival or, alternatively, represent an evolutionary pathway for cancer cells to adapt to changes in the external environment. Moreover, this review summarizes recent advancements in treatment approaches targeting AS-associated drug resistance, focusing on cis-acting regulatory elements, trans-acting factors, and specific spliced variants. Collectively, gaining an in-depth understanding of the mechanisms underlying aberrant alternative splicing events and developing strategies to target this process hold great promise for overcoming cancer drug resistance.