Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.

中文翻译：

---

通过SRF-MKL1的非规范性刺猬通路激活可促进基底细胞癌的耐药性。

刺猬通路依赖性癌症可通过编码规范性刺猬通路成分的基因突变而逃避平滑化（SMO）抑制；然而，大约50％的耐药性基底细胞癌（BCC）缺少这些基因的其他变体。在这里，我们使用人类和小鼠耐药BCC的多维基因组学分析，来确定由转录因子血清反应因子（SRF）驱动的非规范性刺猬激活途径。主动SRF及其辅助激活因子巨核细胞白血病1（MKL1）与刺猬靶基因附近的DNA结合，并与刺猬蛋白转录因子神经胶质瘤相关癌基因家族锌指1（GLI1）形成先前未知的蛋白复合物，从而导致GLI1转录活性的扩增。我们显示，通过Rho和formin家族成员Diaphanous（mDia）的细胞骨架激活对于SRF-MKL驱动的GLI1激活和肿瘤细胞生存力是必需的。值得注意的是，核MKL1染色可作为小鼠和人类受试者肿瘤中的生物标志物，预测肿瘤对MKL抑制剂的反应能力，从而突出了靶向该途径的治疗潜力。因此，我们的研究首次阐明了细胞骨架激活驱动的转录作为对抗耐药性恶性肿瘤的个性化治疗靶标。