Hedgehog pathway-dependent cancers can escape smoothened (SMO) inhibition through canonical pathway mutations, however, 50% of resistant BCCs lack additional variants in hedgehog genes. Here we use multi-dimensional genomics in human and mouse resistant BCCs to identify a non-canonical hedgehog activation pathway driven by the transcription factor, serum response factor (SRF). Active SRF along with its co-activator megakaryoblastic leukemia 1 (MKL1) form a novel protein complex and share chromosomal occupancy with the hedgehog transcription factor GLI1, causing amplification of GLI1 transcriptional activity. We show cytoskeletal activation by Rho and the formin family member Diaphanous (mDia) are required for SRF/MKL-driven GLI1 activation and tumor cell viability. Remarkably, we use nuclear MKL1 staining in mouse and human patient tumors to define drug responsiveness to MKL inhibitors highlighting the therapeutic potential of targeting this pathway. Thus, our studies illuminate for the first time cytoskeletal-driven transcription as a personalized therapeutic target to combat drug resistant malignancies.

Highlights d Acetylated GLI1 accumulates on the lamina via LAP2b to facilitate nuclear retention d LAP2 isoforms compete to bind GLI1 through a shared LEMlike:zinc finger interaction d LAP2a forms an activating complex with HDAC1 to deacetylate/activate GLI1 A nuclear chaperoning system regulates movement of the transcription factor GLI1 between the nuclear lamina and nucleoplasm to achieve maximal activation.

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The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU’s role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise.

Purpose: The mainstay of treatment for basal cell carcinoma (BCC) is surgical excision, which can result in significant associated morbidity, particularly for patients with recurrent tumors. We previously conducted a drug repositioning screen using molecular data from human BCCs and identified histone deacetylase (HDAC) inhibitors as a potential treatment for BCC. Here we conduct the first proof-of-principle study of a topical pan-HDAC inhibitor, remetinostat, in human BCC. Patients and Methods: We conducted a phase II, open-label, single-arm, single-institution trial of a topical HDAC inhibitor. Participants with at least one BCC were recruited. All participants applied 1% remetinostat gel three times daily for 6 weeks, with measurements of tumor diameter conducted at baseline and week 8. Surgical excision of the remaining tumor was conducted at the end of the study and microscopic evaluation was performed. Results: Thirty-three per-protocol tumors from 25 participants were included in the analysis. The overall response rate, defined as the proportion of tumors achieving more than 30% decrease in the longest diameter from baseline to week 8, was 69.7% [90% confidence interval (CI), 54%–82.5%]. On pathologic examination, 54.8% of tumors demonstrated complete resolution. Pharmacodynamic analysis demonstrated similar levels of acetylated histone H3 in skin tissue before and after treatment, however, phosphorylation was increased. No systemic adverse events were reported. Conclusions: The HDAC inhibitor remetinostat is a well-tolerated and effective topical treatment for reducing BCC disease burden in a clinically significant manner. This provides in-human validation of HDAC inhibitors as a therapy for BCC.

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In the cases detailed herein, diagnosis and treatment of melanomas were delayed because of both state stay at home recommendations as well as patient preference to minimize appointments. These cases were diagnosed after the shutdown in Massachusetts, which was one of the harder hit regions with the initial COVID-19 wave. At that time, personal protective equipment (PPE) and knowledge on virus transmission were limited. However, with improved COVID-19 resources, it is important to counsel patients who are nervous about seeking care, especially those with new tumors, about measures implemented to mitigate COVID-19 transmission, including PPE, staff vaccination and testing programs, and minimizing patient interactions.The COVID-19 pandemic presents new obstacles in the treatment of cancer. Delays in care are multifactorial, but identifying patients who are worried about seeking care and providing education on mitigation strategies could help to minimize delays resulting in adverse outcomes.