Desai Bina, Miti Tatiana, Prabhakaran Sandhya, Miroshnychenko Daria, Henry Menkara, Marusyk Viktoriya, Kumar Pragya, Ozakinci Hilal, Gatenbee Chandler, Bui Marilyn, Boyle Theresa A, Scott Jacob, Altrock Philipp M, Haura Eric, Anderson Alexander R A, Basanta David, Marusyk Andriy
Department of Tumor Microenvironment and Metastasis, H Lee Moffitt Cancer Centre and Research Institute; Tampa, FL, USA.
Cancer Biology Ph.D. Program, University of South Florida; Tampa, FL, USA.
Res Sq. 2025 Apr 24:rs.3.rs-6264377. doi: 10.21203/rs.3.rs-6264377/v1.
Despite inducing strong and durable clinical responses, targeted therapies do not eliminate advanced cancers, as a subset of tumor cells survives within residual tumors, eventually developing resistance. The ability of tumor cells to avoid therapeutic elimination can be mediated both by cell-intrinsic and microenvironmental mechanisms. Whilst the specific molecular mediators of cell-intrinsic and microenvironmental resistance are well understood, their relative contribution to therapeutic responses remains poorly defined. Using spatial histological inferences from experimental models of ALK+ NSCLC, we found that peristromal niches protected tumor cells from therapeutic elimination in vivo, enabling in vivo persistence. Whereas the development of bona fide resistance is associated with the development of the development of cell-intrinsic resistance, relapse of tumor growth reflects a combined effect of both cell-intrinsic and microenvironmental mechanisms. Mechanistically, the protective effect of the peristromal niche is not reducible to a single mechanism, instead reflecting a combined effect of multiple juxtacrine and paracrine mediators. The lack of reducibility to a single molecular mediator presents an obvious challenge to the therapeutic paradigms of targeting individual resistance mechanisms. We found that this challenge could be mitigated by shifting the therapeutic focus to orthogonal collateral sensitivities of residual tumors. Exploiting adaptive upregulation of HER2, associated with both cell-intrinsic and microenvironmental persistence, using the antibody-drug conjugate T-DXd strongly enhanced the effect of targeted therapies and suppressed the development of resistance.
尽管靶向疗法能引发强烈且持久的临床反应，但无法消除晚期癌症，因为肿瘤细胞的一个亚群会在残留肿瘤中存活下来，最终产生耐药性。肿瘤细胞避免被治疗清除的能力可由细胞内在机制和微环境机制介导。虽然细胞内在和微环境耐药的具体分子介质已为人熟知，但其对治疗反应的相对贡献仍不清楚。利用ALK+非小细胞肺癌实验模型的空间组织学推断，我们发现肿瘤周围微环境龛在体内保护肿瘤细胞免受治疗清除，使其能在体内持续存在。真正的耐药性发展与细胞内在耐药性的发展相关，而肿瘤生长的复发反映了细胞内在机制和微环境机制的综合作用。从机制上讲，肿瘤周围微环境龛的保护作用不能归结为单一机制，而是反映了多种旁分泌和自分泌介质的综合作用。无法归结为单一分子介质这一情况对针对个体耐药机制的治疗模式构成了明显挑战。我们发现，将治疗重点转向残留肿瘤的正交 collateral 敏感性可以缓解这一挑战。利用与细胞内在和微环境持久性相关的HER2适应性上调，使用抗体药物偶联物T-DXd可显著增强靶向疗法的效果并抑制耐药性的发展。
