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Recent Developments and Challenges in Molecular-Targeted Therapy of Non-Small-Cell Lung Cancer

Rohilla S, Singh M, Alzarea SI, Almalki WH, Al-Abbasi FA, Kazmi I, et al.

J Environ Pathol Toxicol Oncol, 2023;42(1):27-50.
PMID: 36734951 DOI: 10.1615/JEnvironPatholToxicolOncol.2022042983

Treatment of lung cancer with conventional therapies, which include radiation, surgery, and chemotherapy results in multiple undesirable adverse or side effects. The major clinical challenge in developing new drug therapies for lung cancer is resistance, which involves mutations and disturbance in various signaling pathways. Molecular abnormalities related to epidermal growth factor receptor (EGFR), v-Raf murine sarcoma viral oncogene homolog B1 (B-RAF) Kirsten rat sarcoma virus (KRAS) mutations, translocation of the anaplastic lymphoma kinase (ALK) gene, mesenchymal-epithelial transition factor (MET) amplification have been studied to overcome the resistance and to develop new therapies for non-small cell lung cancer (NSCLC). But, inevitable development of resistance presents limits the clinical benefits of various new drugs. Here, we review current progress in the development of molecularly targeted therapies, concerning six clinical biomarkers: EGFR, ALK, MET, ROS-1, KRAS, and B-RAF for NSCLC treatment.
Fulltext Effect of Secretion Efficiency of Mutant KRAS Neoantigen by Lactococcus lactis on the Immune Response of a Mucosal Vaccine Delivery Vehicle Targeting Colorectal Cancer

Alias NAR, Hoo WPY, Siak PY, Othman SS, Mohammed Alitheen NB, In LLA, et al.

Int J Mol Sci, 2023 May 18;24(10).
PMID: 37240273 DOI: 10.3390/ijms24108928

Colorectal cancer (CRC) is often caused by mutations in the KRAS oncogene, making KRAS neoantigens a promising vaccine candidate for immunotherapy. Secreting KRAS antigens using live Generally Recognized as Safe (GRAS) vaccine delivery hosts such as Lactococcus lactis is deemed to be an effective strategy in inducing specific desired responses. Recently, through the engineering of a novel signal peptide SPK1 from Pediococcus pentosaceus, an optimized secretion system was developed in the L. lactis NZ9000 host. In this study, the potential of the L. lactis NZ9000 as a vaccine delivery host for the production of two KRAS oncopeptides (mutant 68V-DT and wild-type KRAS) through the use of the signal peptide SPK1 and its mutated derivative (SPKM19) was investigated. The expression and secretion efficiency analyses of KRAS peptides from L. lactis were performed in vitro and in vivo in BALB/c mice. Contradictory to our previous study using the reporter staphylococcal nuclease (NUC), the yield of secreted KRAS antigens mediated by the target mutant signal peptide SPKM19 was significantly lower (by ~1.3-folds) compared to the wild-type SPK1. Consistently, a superior elevation of IgA response against KRAS aided by SPK1 rather than mutant SPKM19 was observed. Despite the lower specific IgA response for SPKM19, a positive IgA immune response from mice intestinal washes was successfully triggered following immunization. Size and secondary conformation of the mature proteins are suggested to be the contributing factors for these discrepancies. This study proves the potential of L. lactis NZ9000 as a host for oral vaccine delivery due to its ability to evoke the desired mucosal immune response in the gastrointestinal tract of mice.
Fulltext Mutated HRAS Activates YAP1-AXL Signaling to Drive Metastasis of Head and Neck Cancer

Jagadeeshan S, Prasad M, Badarni M, Ben-Lulu T, Liju VB, Mathukkada S, et al.

Cancer Res, 2023 Apr 04;83(7):1031-1047.
PMID: 36753744 DOI: 10.1158/0008-5472.CAN-22-2586

The survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts, and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also regulated AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.
SIGNIFICANCE: Mutant HRAS drives metastasis of head and neck cancer by switching off the Hippo pathway to activate the YAP1-AXL axis and to stimulate lymphovascular angiogenesis.
In silico and saturation transfer difference NMR approaches to unravel the binding mode of an andrographolide derivative to K-Ras oncoprotein

Quah SY, Tan MS, Ho KL, Manan NA, Gorfe AA, Deb PK, et al.

Future Med Chem, 2020 09;12(18):1611-1631.
PMID: 32892640 DOI: 10.4155/fmc-2020-0104

Background: Andrographolide and its benzylidene derivatives, SRJ09 and SRJ23, potentially bind oncogenic K-Ras to exert anticancer activity. Their molecular interactions with K-Ras oncoproteins that lead to effective biological activity are of major interest. Methods & results: In silico docking and molecular dynamics simulation were performed using Glide and Desmond, respectively; while saturation transfer difference NMR was performed using GDP-bound K-RasG12V. SRJ23 was found to bind strongly and selectively to K-RasG12V, by anchoring to a binding pocket (namely p2) principally via hydrogen bond and hydrophobic interactions. The saturation transfer difference NMR analysis revealed the proximity of protons of functional moieties in SRJ23 to K-RasG12V, suggesting positive binding. Conclusion: SRJ23 binds strongly and interacts stably with K-RasG12V to exhibit its inhibitory activity.
Increased SPRY1 expression activates NF-κB signaling and promotes pancreatic cancer progression by recruiting neutrophils and macrophages through CXCL12-CXCR4 axis

Shi T, Li X, Zheng J, Duan Z, Ooi YY, Gao Y, et al.

Cell Oncol (Dordr), 2023 Aug;46(4):969-985.
PMID: 37014552 DOI: 10.1007/s13402-023-00791-z

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high mortality rate, in which about 90% of patients harbor somatic oncogenic point mutations in KRAS. SPRY family genes have been recognized as crucial negative regulators of Ras/Raf/ERK signaling. Here, we investigate the expression and role of SPRY proteins in PDAC.
METHODS: Expression of SPRY genes in human and mice PDAC was analyzed using The Cancer Genome Atlas and Gene Expression Omnibus datasets, and by immunohistochemistry analysis. Gain-of-function, loss-of-function of Spry1 and orthotopic xenograft model were adopted to investigate the function of Spry1 in mice PDAC. Bioinformatics analysis, transwell and flowcytometry analysis were used to identify the effects of SPRY1 on immune cells. Co-immunoprecipitation and K-ras4B G12V overexpression were used to identify molecular mechanism.
RESULTS: SPRY1 expression was remarkably increased in PDAC tissues and positively associated with poor prognosis of PDAC patients. SPRY1 knockdown suppressed tumor growth in mice. SPRY1 was found to promote CXCL12 expression and facilitate neutrophil and macrophage infiltration via CXCL12-CXCR4 axis. Pharmacological inhibition of CXCL12-CXCR4 largely abrogated the oncogenic functions of SPRY1 by suppressing neutrophil and macrophage infiltration. Mechanistically, SPRY1 interacted with ubiquitin carboxy-terminal hydrolase L1 to induce activation of nuclear factor κB signaling and ultimately increase CXCL12 expression. Moreover, SPRY1 transcription was dependent on KRAS mutation and was mediated by MAPK-ERK signaling.
CONCLUSION: High expression of SPRY1 can function as an oncogene in PDAC by promoting cancer-associated inflammation. Targeting SPRY1 might be an important approach for designing new strategy of tumor therapy.
Effects of Alkoxy Chain Length and 1-Hydroxy Group on Anticolorectal Cancer Activity of 2-Bromoalkoxyanthraquinones

Mekzali NW, Chee CW, Abdullah I, Lee YK, Rashid NN, Lee VS, et al.

Med Chem, 2023;19(9):897-905.
PMID: 37046198 DOI: 10.2174/1573406419666230410134213

BACKGROUND: KRAS and p53 are two of the most common genetic alterations associated with colorectal cancer. New drug development targeting these mutated genes in colorectal cancer may serve as a potential treatment avenue to the current regimen.
OBJECTIVE: The objective of the present study was to investigate the effects of alkoxy chain length and 1-hydroxy group on anticolorectal cancer activity of a series of 2-bromoalkoxyanthraquinones and corroborate it with their in silico properties.
METHODS: In vitro anticancer activity of 2-bromoalkoxyanthraquinones was evaluated against HCT116, HT29, and CCD841 CoN cell lines, respectively. Molecular docking was performed to understand the interactions of these compounds with putative p53 and KRAS targets (7B4N and 6P0Z).
RESULTS: 2-Bromoalkoxyanthraquinones with the 1-hydroxy group were proven to be more active than the corresponding counterparts in anticancer activity. Among the tested compounds, compound 6b with a C3 alkoxy chain exhibited the most promising antiproliferation activity against HCT116 cells (IC50 = 3.83 ± 0.05 μM) and showed high selectivity for HCT116 over CCD841 CoN cells (SI = 45.47). The molecular docking reveals additional hydrogen bonds between the 1-hydroxy group of 6b and the proteins. Compound 6b has adequate lipophilicity (cLogP = 3.27) and ligand efficiency metrics (LE = 0.34; LLE = 2.15) close to the proposed acceptable range for an initial hit.
CONCLUSION: This work highlights the potential of the 1-hydroxy group and short alkoxy chain on anticolorectal cancer activity of 2-bromoalkoxyanthraquinones. Further optimisation may be warranted for compound 6b as a therapeutic agent against colorectal cancer.
Para-phenylenediamine-induces apoptosis via a pathway dependent on PTK-Ras-Raf-JNK activation but independent of the PI3K/Akt pathway in NRK-52E cells

Kasi RA, Moi CS, Kien YW, Yian KR, Chin NW, Yen NK, et al.

Mol Med Rep, 2015 Mar;11(3):2262-8.
PMID: 25411820 DOI: 10.3892/mmr.2014.2979

para‑Phenylenediamine (p‑PD) is a potential carcinogen, and widely used in marketed hair dye formulations. In the present study, the role of the protein tyrosine kinase (PTK)/Ras/Raf/c‑Jun N‑terminal kinase (JNK) and phosphoinositide 3‑kinase (PI3k)/protein kinase B (Akt) pathways on the growth of NRK‑52E cells was investigated. The results demonstrated that p‑PD reduced cell viability in a dose‑dependent manner. The cell death due to apoptosis was confirmed by cell cycle analysis and an Annexin‑V‑fluorescein isothiocyanate binding assay. Subsequent to staining with 2',7'‑dichlorofluorescin diacetate, the treated cells demonstrated a significant increase in reactive oxygen species (ROS) generation compared with the controls. The effects of p‑PD on the signalling pathways were analysed by western blotting. p‑PD‑treated cells exhibited an upregulated phospho‑stress‑activated protein kinase/JNK protein expression level and downregulated Ras and Raf protein expression levels; however, Akt, Bcl‑2, Bcl‑XL and Bad protein expression levels were not significantly altered compared with the control. In conclusion, p‑PD induced apoptosis by a PTK/Ras/Raf/JNK‑dependent pathway and was independent of the PI3K/Akt pathway in NRK‑52E cells.
Design and synthesis of mono and bicyclic tetrapeptides thioester as potent inhibitor of histone deacetylases

Hoque MA, Islam MS, Islam MN, Kato T, Nishino N, Ito A, et al.

Amino Acids, 2014 Oct;46(10):2435-44.
PMID: 25048030 DOI: 10.1007/s00726-014-1800-5

Inhibitors of histone deacetylases (HDACs) are a promising class of anticancer agents that have an effect on gene regulation. The naturally occurring cyclic depsipeptide FK228 containing disulfide and Largazole possessing thioester functionalities act as pro-drugs and share the same HDAC inhibition mechanism in cell. Inspired from these facts, we have reported bicyclic tetrapeptide disulfide HDAC inhibitors resembling FK228 with potent activity and enhanced selectivity. In the present study, we report the design and synthesis of several mono and bicyclic tetrapeptide thioester HDAC inhibitors that share the inhibition mechanism similar to Largazole. Most of the compounds showed HDAC1 and HDAC4 inhibition and p21 promoting activity in nanomolar ranges. Among these the monocyclic peptides 1, 2 and bicyclic peptide, 4 are notable demanding more advanced research to be promising anticancer drug candidates.