Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies
; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients ...with hepatocellular carcinoma
. The induction of senescence may represent a strategy for the treatment of cancer, especially when combined with a second drug that selectively eliminates senescent cancer cells (senolysis)
. Here, using a kinome-focused genetic screen, we show that pharmacological inhibition of the DNA-replication kinase CDC7 induces senescence selectively in liver cancer cells with mutations in TP53. A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR signalling, and selective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition
is blocked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, we show that treatment with combined inhibition of of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer.
Liver cancer is the fourth most common cause of cancer‐related death worldwide, with hepatocellular carcinoma (HCC) being the main primary malignancy affecting the liver. Unfortunately, there are ...still limited therapeutic options for HCC, and even the latest advances have only increased the overall survival modestly. Thus, new treatment strategies and rational drug combinations are urgently needed. Reactivation of receptor tyrosine kinases (RTK) has been described as a mechanism of intrinsic resistance to targeted therapies in a variety of cancers, including inhibitors of mTOR. The design of rational combination therapies to overcome this type of resistance is complicated by the notion that multiple RTK can be upregulated during the acquisition of resistance. SHP2, encoded by the gene PTPN11, acts downstream of virtually all RTK, and has proven to be a good target for small molecule inhibitors. Here, we report activation of multiple RTK upon mTOR inhibition in HCC which, through SHP2, leads to reactivation of the mTOR pathway. We show that co‐inhibition of both mTOR and SHP2 is highly synergistic in vitro by triggering apoptosis. More importantly, the combination is well‐tolerated and outperforms the monotherapies in impairing tumor growth in multiple HCC mouse models. Our findings suggest a novel rational combination therapy for the treatment of HCC.
We show that, upon mTOR inhibition with AZD8055, there is upregulation of several receptor tyrosine kinases. As consequence, SHP2 signals through the mTOR pathway. Hence, dual blockade of SHP2 and mTOR can effectively suppress the mTOR pathway and drive anti‐cancer response, both in vitro and in vivo, in several hepatocellular carcinoma models.
Precision oncology aims to distinguish which patients are eligible for a specific treatment in order to achieve the best possible outcome. In the last few years, genetic screens have shown their ...potential to find the new targets and drug combinations as well as predictive biomarkers for response and/or resistance to cancer treatment. In this review, we outline how precision oncology is changing over time and describe the different applications of genetic screens. Finally, we present some practical examples that describe the utility and the limitations of genetic screens in precision oncology.
Over 90% of pancreatic cancers present mutations in KRAS, one of the most common oncogenic drivers overall. Currently, most KRAS mutant isoforms cannot be targeted directly. Moreover, targeting ...single RAS downstream effectors induces adaptive resistance mechanisms. We report here on the combined inhibition of SHP2, upstream of KRAS, using the allosteric inhibitor RMC-4550 and of ERK, downstream of KRAS, using LY3214996. This combination shows synergistic anti-cancer activity in vitro, superior disruption of the MAPK pathway, and increased apoptosis induction compared with single-agent treatments. In vivo, we demonstrate good tolerability and efficacy of the combination, with significant tumor regression in multiple pancreatic ductal adenocarcinoma (PDAC) mouse models. Finally, we show evidence that 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can be used to assess early drug responses in animal models. Based on these results, we will investigate this drug combination in the SHP2 and ERK inhibition in pancreatic cancer (SHERPA; ClinicalTrials.gov: NCT04916236) clinical trial, enrolling patients with KRAS-mutant PDAC.
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•SHP2 and ERK co-inhibition is synergistic and triggers apoptosis in PDAC in vitro•The combination is tolerated and promotes tumor regression in multiple in vivo models•Non-invasive PET-CT scans can monitor early response to the therapy•The SHERPA phase 1a/1b trial will investigate the combination clinically
KRAS mutant pancreatic tumors have poor prognosis and few therapeutic options. Here, Frank et al. show that the combination of RMC4550 (SHP2 inhibitor) and LY3214996 (ERK inhibitor) effectively impairs tumor growth and induces tumor regression in multiple in vivo models of PDAC.
Discovering biomarkers of drug response and finding powerful drug combinations can support the reuse of previously abandoned cancer drugs in the clinic. Indisulam is an abandoned drug that acts as a ...molecular glue, inducing degradation of splicing factor RBM39 through interaction with CRL4
Here, we performed genetic and compound screens to uncover factors mediating indisulam sensitivity and resistance. First, a dropout CRISPR screen identified SRPK1 loss as a synthetic lethal interaction with indisulam that can be exploited therapeutically by the SRPK1 inhibitor SPHINX31. Moreover, a CRISPR resistance screen identified components of the degradation complex that mediate resistance to indisulam: DCAF15, DDA1, and CAND1. Last, we show that cancer cells readily acquire spontaneous resistance to indisulam. Upon acquiring indisulam resistance, pancreatic cancer (Panc10.05) cells still degrade RBM39 and are vulnerable to BCL-xL inhibition. The better understanding of the factors that influence the response to indisulam can assist rational reuse of this drug in the clinic.
•Very high free ellagic acid (EA) intake does not enhance EA bioavailability.•pH, ellagitannin precursor and proteins are critical for EA bioavailability.•Plasma EA pharmacokinetics show high ...interindividual variability.•Free EA rarely exceeds 100 nM in human plasma but it is higher than previously thought.•We provide useful data to design in vitro assays using physiological concentrations.
Ellagic acid (EA) is a polyphenol that must be released from the non-bioavailable ellagitannins in pomegranates, walnuts or strawberries to be absorbed. To estimate whether EA bioavailability could be improved after consumption of a high free EA amount, we conducted a crossover pharmacokinetic study in healthy volunteers that consumed two pomegranate extracts providing either 130 mg punicalagin+524 mg EA (PE-1) or 279 mg punicalagin+25 mg EA (PE-2). Targeted metabolomics (UPLC-ESI-qTOF-MS/MS) identified plasma free EA but not phase-II conjugates. EA pharmacokinetics showed high interindividual variability. Cmax ranged from 12 to 360 nM (PE-1: 74.8 ± 54.4 nM; PE-2: 64.1 ± 76.8 nM). In vitro digestion supported in vivo results. EA bioavailability was limited by the ellagitannin, pH and protein environment. A higher free EA intake does not enhance its bioavailability but promotes urolithin production. Bioavailability of EA, as the unchanged fraction that reaches the systemic circulation, is not as low as previously thought.
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