Biology subjects

Gordan, J.

Publications and source records attributed to Gordan, J..

4 recordsLinked to original sources

bioRxiv2026

A transcriptional signature of LKB1 functional loss defines a large, therapeutically addressable patient population across human cancers

Loss of the tumor suppressor LKB1 (STK11) drives metabolic reprogramming and immune evasion, but its clinical footprint is defined almost entirely by somatic mutation and deletion. Because emerging therapies aim to reactivate this pathway in structurally wild-type tumors, defining the full LKB1-deficient population (including tumors silenced by non-genomic mechanisms) is a prerequisite for patient selection. We derived a 30-gene transcriptional signature of LKB1 functional loss, training on genomically-defined STK11 loss in lung adenocarcinoma and validating in an independent squamous cohort (AUROC 0.926). It transferred to four independent non-TCGA LUAD cohorts (AUROC 0.92-0.98), outperforming the published Kaufman 16-gene classifier. Critically, restoring wild-type LKB1 in LKB1-mutant NSCLC lines reversed the signature while a kinase-dead mutant did not, establishing that it reads out LKB1 kinase function, not merely mutation status. Applied pan-cancer, the signature identified functional LKB1 loss in wild-type tumors at 7.2%, expanding total LKB1-loss prevalence 3.7-fold over genomic loss alone (2.7% [->] 9.9%), largest in esophageal, colorectal, endometrial and cutaneous cancers. This population is decoupled from LKB1 mutation and deletion frequency, yet enriched in BRAF-mutant colorectal (25% signature-positive) and HER2-amplified breast (21% signature-positive) cancers: readily-testable subgroups for screening. In lung adenocarcinoma, signature positivity rose across a co-mutation gradient from 6% background to 15% in KRAS-mutant, 35% in NRF2-pathway-mutant (KEAP1 or NFE2L2), to 64% in KRAS/NRF2 co-mutant tumors. Similar to KRAS/LKB1 co-mutant tumors, LKB1 wild-type but signature-high tumors were immune-cold, correlating negatively with antigen-presentation, interferon-{gamma} and T-cell-inflamed programs in multiple independent lung cancer cohorts. These results define a broad set of tumors with LKB1 functional loss that may open up new avenues for precision therapeutics.

cancer biology↗

bioRxiv2023

Recruitment of BAG2 to DNAJ-PKAc scaffolds promotes cell survival and resistance to drug-induced apoptosis in fibrolamellar carcinoma

The DNAJ-PKAc fusion kinase is a defining feature of the adolescent liver cancer fibrolamellar carcinoma (FLC). A single lesion on chromosome 19 generates this mutant kinase by creating a fused gene encoding the chaperonin binding domain of Hsp40 (DNAJ) in frame with the catalytic core of protein kinase A (PKAc). FLC tumors are notoriously resistant to standard chemotherapies. Aberrant kinase activity is assumed to be a contributing factor. Yet recruitment of binding partners, such as the chaperone Hsp70, implies that the scaffolding function of DNAJ- PKAc may also underlie pathogenesis. By combining proximity proteomics with biochemical analyses and photoactivation live-cell imaging we demonstrate that DNAJ-PKAc is not constrained by A-kinase anchoring proteins. Consequently, the fusion kinase phosphorylates a unique array of substrates. One validated DNAJ-PKAc target is the Bcl-2 associated athanogene 2 (BAG2), a co-chaperone recruited to the fusion kinase through association with Hsp70. Immunoblot and immunohistochemical analyses of FLC patient samples correlate increased levels of BAG2 with advanced disease and metastatic recurrences. BAG2 is linked to Bcl-2, an anti-apoptotic factor that delays cell death. Pharmacological approaches tested if the DNAJ- PKAc/Hsp70/BAG2 axis contributes to chemotherapeutic resistance in AML12DNAJ-PKAc hepatocyte cell lines using the DNA damaging agent etoposide and the Bcl-2 inhibitor navitoclax. Wildtype AML12 cells were susceptible to each drug alone and in combination. In contrast, AML12DNAJ-PKAc cells were moderately affected by etoposide, resistant to navitoclax, but markedly susceptible to the drug combination. These studies implicate BAG2 as a biomarker for advanced FLC and a chemotherapeutic resistance factor in DNAJ-PKAc signaling scaffolds.

cancer biology↗

bioRxiv2023

HBV rewires liver cancer signaling by altering PP2A complexes

Infection by hepatitis B virus (HBV) increases risk for liver cancer by inducing inflammation, cellular stress and cell death. To elucidate the molecular pathways by which HBV promotes cancer development and progression, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human host proteins in hepatocellular carcinoma (HCC). We find that viral proteins target host factors that are preferentially mutated in non-HBV-associated HCC, implicating cancer pathways whose interaction with HBV plays a role in HCC. Focusing on proteins that directly interact with the HBV oncoprotein X (HBx), we show that HBx remodels the PP2A phosphatase complex, altering its effect on tumor signaling. HBx excludes striatin-family regulatory subunits from PP2A, causing Hippo kinase activation and unmasking a requirement for mTOR complex 2 to maintain expression of the YAP oncoprotein in HCC. Thus, HBV rewires HCC to expose potentially targetable signaling dependencies. SignificancePrecision medicine has revolutionized cancer treatment but remains elusive for HCC. We used proteomics to define HBV/host interactions and integrated them with HCC mutations. The results implicate modifiers of HCC behavior via remodeling of host complexes and illuminate new biological mechanisms in advanced disease for therapeutic investigation.

cancer biology↗

bioRxiv2017

Kinome rewiring reveals AURKA is a molecular barrier to the efficacy of PI3K/mTOR-pathway inhibitors in breast cancer

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest. We hypothesized that dynamic changes in signaling, including adaptation and feedback, limit drug efficacy. Using a quantitative chemoproteomics approach we mapped dynamic changes in the kinome in response to various agents and identified signaling changes that correlate with drug sensitivity. Measurement of dynamics across a panel of breast cancer cell lines identified that maintenance of CDK4 and AURKA activity was associated with drug resistance. We tested whether incomplete inhibition of CDK4 or AURKA was a source of therapy failure and found that inhibition of either was sufficient to sensitize most breast cancer cells to PI3K, AKT, and mTOR inhibitors. In particular, drug combinations including the AURKA inhibitor MLN8237 were highly synergistic and induced apoptosis through enhanced suppression of mTOR signaling to S6 and 4E-BP1 leading to tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of target therapy and indicates that Aurora kinase co-inhibition could unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer.

cancer biology↗