Histone Deacetylase 6 Inhibition Exploits Selective Metabolic Vulnerabilities in LKB1 Mutant, KRAS Driven NSCLC.

INTRODUCTION: In KRAS-mutant NSCLC, co-occurring alterations in LKB1 confer a negative prognosis compared with other mutations such as TP53. LKB1 is a tumor suppressor that coordinates several signaling pathways in response to energetic stress. Our recent work on pharmacologic and genetic inhibition of histone deacetylase 6 (HDAC6) revealed the impaired activity of numerous enzymes involved in glycolysis. On the basis of these previous findings, we explored the therapeutic window for HDAC6 inhibition in metabolically-active KRAS-mutant lung tumors. METHODS: Using cell lines derived from mouse autochthonous tumors bearing the KRAS/LKB1 (KL) and KRAS/TP53 mutant genotypes to control for confounding germline and somatic mutations in human models, we characterize the metabolic phenotypes at baseline and in response to HDAC6 inhibition. The impact of HDAC6 inhibition was measured on cancer cell growth in vitro and on tumor growth in vivo. RESULTS: Surprisingly, KL-mutant cells revealed reduced levels of redox-sensitive cofactors at baseline. This is associated with increased sensitivity to pharmacologic HDAC6 inhibition with ACY-1215 and blunted ability to increase compensatory metabolism and buffer oxidative stress. Seeking synergistic metabolic combination treatments, we found enhanced cell killing and antitumor efficacy with glutaminase inhibition in KL lung cancer models in vitro and in vivo. CONCLUSIONS: Exploring the differential metabolism of KL and KRAS/TP53-mutant NSCLC, we identified decreased metabolic reserve in KL-mutant tumors. HDAC6 inhibition exploited a therapeutic window in KL NSCLC on the basis of a diminished ability to compensate for impaired glycolysis, nominating a novel strategy for the treatment of KRAS-mutant NSCLC with co-occurring LKB1 mutations.

Inhibiting GLUTtony in cancer.

In this issue of Cell Chemical Biology, Olszewski et al. (2022) address the challenge of developing small molecules to inhibit glucose uptake in cancer. They characterize a novel pan-GLUT inhibitor that suppresses tumor growth and uncover how cancer cells can adapt to glucose restriction.

Dexamethasone implant migration in an eye with congenital glaucoma: A case report and review of the literature.

INTRODUCTION: The dexamethasone (DEX) implant is an FDA approved treatment for diabetic macular edema, non-infectious posterior uveitis, and macular edema secondary to branch or central retinal vein occlusions. We describe a case of anterior chamber (AC) migration of a DEX implant in a patient with a history of congenital glaucoma and perform a review of the literature on this particular complication, summarizing the common risk factors, subsequent complications, and management options. CASE DESCRIPTION: A 46-year-old female with a history of congenital glaucoma, status post cataract extraction with insertion of intraocular lens, pars plana vitrectomy, and Baerveldt tube implant in the left eye was referred for post-operative cystoid macular edema (CME). The patient underwent insertion of a DEX implant, resulting in improvement in her CME. After the fourth implant was injected, the patient noticed a white line in her eye while looking in the mirror after doing jumping jacks. Slit lamp examination confirmed migration of the implant into the AC. Ultimately, the patient was taken to the operating room, where her implant was removed via bimanual vitrectomy through an anterior approach. CONCLUSION: This case report and literature review explores the ophthalmic structural changes specific to congenital glaucoma which may have predisposed this eye to anterior migration of the DEX implant. The purpose of this review is to detail the anatomic changes that may increase the risk of anterior chamber implant migration in patients with congenital glaucoma so that physicians may be aware of these risks when selecting patients for this implant.

Porcine acellular dermal matrix (PADM) vascularises after exposure in open necrotic wounds seen after complex hernia repair.

Biological alternatives to synthetic meshes are increasingly utilised in complex abdominal wall reconstruction. There is a lack of evidence demonstrating that non-cross-linked porcine acellular dermal matrix vascularizes and integrates with human tissue in suboptimal wound conditions. We aimed to evaluate these properties in Strattice™ (Life Cell Inc., Branchburg, NJ) following ventral hernia repair. A retrospective review of patients with high-risk ventral hernia repair utilising Strattice™ as an onlay after open component separation was conducted. Patients with postoperative wound exploration and exposure of the onlay were included in this review. One patient underwent punch biopsy for histological analysis. Eleven patients with wound complications necessitating postoperative debridement and exposure of Strattice™ onlay were identified. The onlay was partially debrided in two cases, and one case required complete excision. Vascularisation was clinically evident in 10 of 11 cases (91%) as demonstrated by the presence of granulation tissue and/or the ability to support a skin graft. Histological analysis of one onlay 3 months postoperatively showed neovascularisation and collagen remodelling with minimal inflammatory response. Strattice™ demonstrated resistance to rejection, ability to undergo vascularisation and incorporation into host tissues in sub-optimal wound conditions following ventral hernia repair.