Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor

Romaniello, Donatella; Marrocco, Ilaria; Nataraj, Nishanth Belugali; Ferrer, Irene; Drago-García, Diana; Vaknin, Ilan; Oren, Roni; Lindzen, Moshit; Ghosh, Soma; Kreitman, Matthew; Kittel, Jeanette Clarissa; Gaborit, Nadège; Báez, Gretchen Bergado; Sánchez, Belinda; Pikarsky, Eli; Paz‐Ares, Luis; Yarden, Yosef

doi:10.3390/cancers12092394

Cited by 39 publications

(30 citation statements)

References 54 publications

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“…Clinical trials should determine the mode and duration of citrate sodium administration, its toxicity, and its efficiency. Knowing that numerous patients worldwide have incurable cancers supported by aerobic glycolysis and key oncogenic drivers (such as IGF-1R, Ras/PI3K/Akt, HER2/neu, WNT/β-catenin, TME acidity and EMT) [ 145 , 161 , 162 ], all pathways efficiently counteracted by citrate sodium in preclinical studies, we strongly believe that the citrate strategy we have proposed since many years [ 25 ] should now be considered for clinical trials. In particular, this strategy could increase both the sensitivity to standard chemotherapy drugs and to targeted therapies, whose resistance is mainly supported by the Warburg effect and its oncogenic drivers.…”

Section: Discussion and Therapeutic Perspectivesmentioning

confidence: 99%

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

Icard

Coquerel

et al. 2021

IJMS

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Citrate plays a central role in cancer cells’ metabolism and regulation. Derived from mitochondrial synthesis and/or carboxylation of α-ketoglutarate, it is cleaved by ATP-citrate lyase into acetyl-CoA and oxaloacetate. The rapid turnover of these molecules in proliferative cancer cells maintains a low-level of citrate, precluding its retro-inhibition on glycolytic enzymes. In cancer cells relying on glycolysis, this regulation helps sustain the Warburg effect. In those relying on an oxidative metabolism, fatty acid β-oxidation sustains a high production of citrate, which is still rapidly converted into acetyl-CoA and oxaloacetate, this latter molecule sustaining nucleotide synthesis and gluconeogenesis. Therefore, citrate levels are rarely high in cancer cells. Resistance of cancer cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), is frequently sustained by aerobic glycolysis and its key oncogenic drivers, such as Ras and its downstream effectors MAPK/ERK and PI3K/Akt. Remarkably, in preclinical cancer models, the administration of high doses of citrate showed various anti-cancer effects, such as the inhibition of glycolysis, the promotion of cytotoxic drugs sensibility and apoptosis, the neutralization of extracellular acidity, and the inhibition of tumors growth and of key signalling pathways (in particular, the IGF-1R/AKT pathway). Therefore, these preclinical results support the testing of the citrate strategy in clinical trials to counteract key oncogenic drivers sustaining cancer development and resistance to anti-cancer therapies.

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Section: Discussion and Therapeutic Perspectivesmentioning

confidence: 99%

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

Icard

Coquerel

et al. 2021

IJMS

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“…Our previous studies showed that treatments of erlotinib‐resistant models with an anti‐EGFR antibody evoke a compensatory response that up‐regulates two EGFR family members, HER2 and HER3 (Mancini et al, 2015). Hence, we combined a TKI and mAbs against EGFR/HER‐family members and observed effective inhibition of erlotinib‐resistant tumors in cell line xenografts (Mancini et al, 2015; Mancini et al, 2018; Romaniello et al, 2018; Romaniello et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Upfront admixing antibodies and EGFR inhibitors preempts sequential treatments in lung cancer models

et al. 2021

Self Cite

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Some antibacterial therapies entail sequential treatments with different antibiotics, but whether this approach is optimal for anti‐cancer tyrosine kinase inhibitors (TKIs) remains open. EGFR mutations identify lung cancer patients who can derive benefit from TKIs, but most patients develop resistance to the first‐, second‐, and third‐generation drugs. To explore alternatives to such whack‐a‐mole strategies, we simulated in patient‐derived xenograft models the situation of patients receiving first‐line TKIs. Monotherapies comprising approved first‐line TKIs were compared to combinations with antibodies specific to EGFR and HER2. We observed uniform and strong superiority of all drug combinations over the respective monotherapies. Prolonged treatments, high TKI dose, and specificity were essential for drug–drug cooperation. Blocking pathways essential for mitosis (e.g., FOXM1), along with downregulation of resistance‐conferring receptors (e.g., AXL), might underlie drug cooperation. Thus, upfront treatments using combinations of TKIs and antibodies can prevent emergence of resistance and hence might replace the widely applied sequential treatments utilizing next‐generation TKIs.

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“…Through similar mechanisms, the combination of a neutralizing anti-HER3 antibody that can clear HER3 from the cell surface, with osimertinib and cetuximab generated similar results. 55 These studies thus further underline the importance of targeting MEK/ERK pathway in preventing and overcoming acquired resistance to osimertinib.…”

Section: Introductionmentioning

confidence: 89%

Managing Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors Through Co-Targeting MEK/ERK Signaling

Yu¹,

Zhao²,

Vallega³

et al. 2021

LCTT

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Although epidermal growth factor receptor (EGFR)-targeted therapy has improved clinical outcomes of patients with advanced non-small-cell lung cancer (NSCLC) carrying activating EGFR mutations, the development of acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs), including the promising third-generation ones, results in disease progression and has become an unavoidable problem that limits patient long-term benefit. The third-generation EGFR-TKIs, osimertinib and almonertinib, are now approved for the treatment of advanced NSCLC patients harboring activating EGFR mutations (first-line) and/or the resistant T790M mutation (second-line). Clinically, appropriate management of acquired resistance to third-generation EGFR-TKIs will substantially improve their long-term efficacy against EGFR-mutant NSCLC. Recent preclinical and clinical studies suggest that activation of the Ras/Raf/MEK/ERK signaling pathway may be an important resistance mechanism and accordingly co-targeting this pathway effectively overcomes and abrogates acquired resistance to third-generation EGFR-TKIs. This review focuses on discussing the scientific rationale for and potential of co-targeting MEK/ERK signaling in delaying and overcoming acquired resistance to third-generation EGFR-TKIs, particularly osimertinib.

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Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor

Cited by 39 publications

References 54 publications

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

Upfront admixing antibodies and EGFR inhibitors preempts sequential treatments in lung cancer models

Managing Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors Through Co-Targeting MEK/ERK Signaling

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