Jackson, K. E. | bioRxiv Science

bioRxiv2025

Targeting ALC1 can safely expand the therapeutic utility of PARP inhibitors across high-grade serous ovarian cancers

Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for homologous recombination-deficient (HRD) high-grade serous ovarian cancers (HGSOCs), but their long-term effectiveness is limited by the emergence of resistance and hematological toxicity. Moreover, PARPi are largely ineffective in HR-proficient HGSOCs, particularly tumors with CCNE1 amplification, which exhibit marked therapeutic resistance and currently lack effective treatment options. Loss of a chromatin remodeling enzyme, Amplified in Liver Cancer 1 (ALC1), has been shown to enhance PARPi sensitivity. However, the clinical contexts in which ALC1 targeting will be clinically meaningful remain elusive. Here we demonstrate that ALC1 loss enhances PARPi sensitivity across HRD and CCNE1-amplified serous ovarian cancer lines, xenograft and patient-derived cells. ALC1 depletion can overcome clinically relevant mechanisms of PARPi resistance while having minimal effects in BRCA-wild-type or heterozygous non-cancerous cells. Consistent with this therapeutic safety, PARPi sensitivity upon ALC1 loss can be reliably predicted by the endogenous levels of phospho-T21 RPA2, a marker for replication stress which is typically higher in ovarian cancer cells compared to their normal counterparts. Together, our studies define the clinical contexts in which the therapeutic utility of PARPi can be expanded by targeting ALC1, whose inhibitors are currently in Phase I clinical trials.

cancer biology↗

bioRxiv2022

Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in vitro and in silico screening of a small library of Phenolic compounds

Melanoma and non-melanoma skin cancers are the most-lethal and commonest forms of skin cancers, that affecting one-fifth of the US population. With the aim of identifying new lead compounds as starting point for attaining cost-effective therapies, a small library of about 90 molecules was screened in vitro against A375, SKMEL-28, A431, SCC-12 skin cancer cell lines. About 35 of them, mainly dihydroquinolines, C-C and C-N linked biphenyls, and substituted methylgallate or aniline derivatives, displayed low-micromolar range activities, primarily against the A431 and SCC-12 squamous carcinoma cell lines, with only a handful of these compounds displaying any activity against the A375 and SKMEL-28 melanoma cell lines. Compounds 11 (A431: IC50 = 5.0 {micro}M, SCC-12: IC50 = 2.9 {micro}M, SKMEL-28: IC50 = 4.9 {micro}M, A375: IC50 = 6.7 {micro}M) and 13 (A431: IC50 = 5.0 {micro}M, SCC-12: IC50 = 3.3 {micro}M, SKMEL-28: IC50 = 13.8 {micro}M, A375: IC50 = 17.1 {micro}M) were the most active across all these cell lines. Furthermore, many of the hit compounds showed little to no activity against mammalian nontumorigenic immortalized HaCaT cells, with a far better selectivity index than cisplatin (a well-known anticancer agent used as a positive control). Compounds 11 and 13 significantly and dose-dependently induced apoptosis of SCC-12 and SK-MEL-28 cells as evidenced by the downregulation of Bcl-2 and upregulation of Bax protein expression levels, and by cleaved caspase-3, caspase-9 and PARP levels. Both agents also significantly reduced scratch wound healing, colony formation, and activated expression levels of major cancer molecular targets such as RSK/AKT/ERK1/2 and S6K1. To provide a better attribute profile for each of the hit molecules, in-silico target(s) prediction, pharmacokinetic and ADMET studies are also reported, together with some preliminary structure-activity relationship outlines. The SwissTargetPrediction web-based tool identified CDK8, CLK4, nuclear receptor ROR, tyrosine protein-kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, as likely targets for these hit compounds. Furthermore, the SwissADME web_tool predicted these compounds to exhibit high GI tract absorption, good skin permeation, and a viable biodegradability profile. To summarize, these data highlight the promising anticancer potential of these small molecules leads, warranting further investigation and/or optimization towards obtaining clinical candidates for combatting both melanoma and non-melanoma skin cancers.

pharmacology and toxicology↗