Tchelougou Daméhan, Malaquin Nicolas, Cardin Guillaume B, Desmul Jordan, Turcotte Simon, Rodier Francis
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) et Institut du Cancer de Montréal, Montreal, QC, Canada.
Département de chirurgie, Université de Montréal, Montreal, QC, Canada.
Front Cell Dev Biol. 2024 Jun 14;12:1368711. doi: 10.3389/fcell.2024.1368711. eCollection 2024.
Malignant Melanoma that resists immunotherapy remains the deadliest form of skin cancer owing to poor clinically lasting responses. Alternative like genotoxic or targeted chemotherapy trigger various cancer cell fates after treatment including cell death and senescence. Senescent cells can be eliminated using senolytic drugs and we hypothesize that the targeted elimination of therapy-induced senescent melanoma cells could complement both conventional and immunotherapies. We utilized a panel of cells representing diverse mutational background relevant to melanoma and found that they developed distinct senescent phenotypes in response to treatment. A genotoxic combination therapy of carboplatin-paclitaxel or irradiation triggered a mixed response of cell death and senescence, irrespective of BRAF mutation profiles. DNA damage-induced senescent melanoma cells exhibited morphological changes, residual DNA damage, and increased senescence-associated secretory phenotype (SASP). In contrast, dual targeted inhibition of Braf and Mek triggered a different mixed cell fate response including senescent-like and persister cells. While persister cells could reproliferate, senescent-like cells were stably arrested, but without detectable DNA damage and senescence-associated secretory phenotype. To assess the sensitivity to senolytics we employed a novel real-time imaging-based death assay and observed that Bcl2/Bcl-XL inhibitors and piperlongumine were effective in promoting death of carboplatin-paclitaxel and irradiation-induced senescent melanoma cells, while the mixed persister cells and senescent-like cells resulting from Braf-Mek inhibition remained unresponsive. Interestingly, a direct synergy between Bcl2/Bcl-XL inhibitors and Braf-Mek inhibitors was observed when used out of the context of senescence. Overall, we highlight diverse hallmarks of melanoma senescent states and provide evidence of context-dependent senotherapeutics that could reduce treatment resistance while also discussing the limitations of this strategy in human melanoma cells.
由于临床持久反应不佳，抵抗免疫疗法的恶性黑色素瘤仍然是最致命的皮肤癌形式。基因毒性或靶向化疗等替代疗法在治疗后会引发各种癌细胞命运，包括细胞死亡和衰老。衰老细胞可以使用衰老溶解药物清除，我们假设靶向清除治疗诱导的衰老黑色素瘤细胞可以补充传统疗法和免疫疗法。我们使用了一组代表与黑色素瘤相关的不同突变背景的细胞，发现它们在治疗后呈现出不同的衰老表型。卡铂-紫杉醇的基因毒性联合疗法或辐射引发了细胞死亡和衰老的混合反应，与BRAF突变谱无关。DNA损伤诱导的衰老黑色素瘤细胞表现出形态变化、残留DNA损伤以及衰老相关分泌表型（SASP）增加。相比之下，对Braf和Mek的双重靶向抑制引发了不同的混合细胞命运反应，包括衰老样细胞和持续存在的细胞。虽然持续存在的细胞可以重新增殖，但衰老样细胞则稳定停滞，但没有可检测到的DNA损伤和衰老相关分泌表型。为了评估对衰老溶解药物的敏感性，我们采用了一种基于实时成像的新型死亡检测方法，观察到Bcl2/Bcl-XL抑制剂和胡椒碱在促进卡铂-紫杉醇和辐射诱导的衰老黑色素瘤细胞死亡方面有效，而由Braf-Mek抑制产生的混合持续存在细胞和衰老样细胞仍然无反应。有趣的是，当在衰老背景之外使用时，观察到Bcl2/Bcl-XL抑制剂和Braf-Mek抑制剂之间存在直接协同作用。总体而言，我们突出了黑色素瘤衰老状态的不同特征，并提供了上下文依赖性衰老治疗的证据，这可能会降低治疗抗性，同时也讨论了该策略在人类黑色素瘤细胞中的局限性。
