Supplementary Material for: Mutant p53 Gain of Function and Chemoresistance: The Role of Mutant p53 in Response to Clinical Chemotherapy

<b><i>Purpose:</i></b> To review mechanisms underlying mutant p53 (mutp53) gain of function (GOF) and mutp53-induced chemoresistance, and to investigate the role of mutp53 in response to clinical chemotherapy. <b><i>Methods:</i></b> We searched the PubMed database for clinical studies from the past decade, including data evaluating the impact of mutp53 in clinical chemotherapy response. <b><i>Results:</i></b> Interactions between mutp53 and transcriptional factors, proteins or DNA structures, as well as epigenetic regulation, contribute to mutp53 GOF. Major mechanisms of mutp53-induced chemoresistance include enhanced drug efflux and metabolism, promoting survival, inhibiting apoptosis, upregulating DNA repair, suppressing autophagy, elevating microenvironmental resistance and inducing a stem-like phenotype. Clinically, mutp53 predicted resistance to chemotherapy in diffuse large B-cell lymphoma, and esophageal and oropharyngeal cancers, but its impact on chronic lymphocytic leukemia was unclear. In bladder cancer, mutp53 did not predict resistance, whereas in some breast and ovarian cancers, it was associated with sensitivity to certain chemotherapeutic agents. <b><i>Conclusion:</i></b> mutp53 has an intricate role in the response to clinical chemotherapy and should not be interpreted in isolation. Furthermore, when predicting tumor response to chemotherapy based on the p53 status, the drugs used should also be taken into consideration. These concepts require further investigation.

<b><i>研究目的：</i></b> 本研究旨在阐明突变型p53（mutant p53，后文简称mutp53）功能获得性（gain of function，GOF）及其诱导化疗耐药的潜在机制，并探讨mutp53在临床化疗应答中的作用。<b><i>研究方法：</i></b> 我们检索了PubMed数据库中近十年的临床研究文献，涵盖评估mutp53对临床化疗应答影响的相关数据。<b><i>研究结果：</i></b> mutp53与转录因子、蛋白质或DNA结构的相互作用，以及表观遗传调控，共同介导了mutp53的功能获得性。mutp53诱导化疗耐药的主要机制包括：增强药物外排与代谢、促进肿瘤细胞存活、抑制细胞凋亡、上调DNA修复能力、抑制自噬、提高微环境耐药性以及诱导干细胞样表型。临床层面，mutp53可预测弥漫大B细胞淋巴瘤、食管癌及口咽癌的化疗耐药性，但对于慢性淋巴细胞白血病的影响尚不明确。在膀胱癌中，mutp53无法预测化疗耐药；而在部分乳腺癌与卵巢癌中，mutp53则与部分化疗药物的敏感性呈正相关。<b><i>研究结论：</i></b> mutp53在临床化疗应答中发挥着复杂的调控作用，不应单独基于其状态进行解读。此外，若基于p53状态预测肿瘤化疗应答，还需综合考量所使用的化疗药物种类。上述结论仍需开展更多研究予以验证。