Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of pre-existing subclones, remains unclear. In EGFR-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires AURKA activity. Non-genetic resistance through the activation of AURKA by its co-activator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in pre-clinical models. Treatment induced activation of AURKA was associated with resistance to EGFR inhibitors in-vitro, in-vivo and in individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA driven residual disease and acquired resistance.
BackgroundLarge cell neuroendocrine tumor (LCNEC) of the lung is a rare and aggressive tumor similar to small cell lung cancer (SCLC). Thus, it is often treated similarly to SCLC in the front-line setting with a platinum doublet. However, treatment for patients beyond the first line remains undefined.Case presentationWe report the case of a patient with stage IB LCNEC (PD-L1 negative but positive for PD-L1 amplification and tumor mutation burden high) who progressed after adjuvant chemotherapy after surgery and subsequent therapy with an antibody drug conjugate targeting a neuroendocrine-specific cell surface marker but achieved a significant and durable response with pembrolizumab, a humanized IgG4 monoclonal anti-PD-1 antibody.ConclusionsImmunotherapy with checkpoint inhibitors is an effective treatment option for patients with metastatic LCNEC, even if PD-L1 expression is negative.
Purpose: Combined mitogen-activated protein kinase (MAPK) pathway inhibition using dual BRAF and MEK inhibitors has prolonged the duration of clinical response in patients with BRAF V600E driven tumors compared to either agent alone. However, resistance frequently arises. Experimental Design:We generated cell lines resistant to dual BRAF/MEK inhibition and utilized a pharmacological synthetic lethal approach to identify a novel, adaptive resistance mechanism mediated through the fibroblast growth factor receptor (FGFR) pathway. Results:In response to drug treatment, transcriptional upregulation of FGF1 results in autocrine activation of FGFR, which sustains extracellular signal-regulated kinases (ERK) activation. FGFR inhibition overcomes resistance to dual BRAF/MEK inhibitors in both cell lines and patient derived xenograft (PDX) models. Abrogation of this bypass mechanism in the front-line setting enhances tumor killing and prevents the emergence of drug-resistant cells. Moreover, clinical data implicate serum FGF1 levels in disease prognosis.
Esophageal cancer remains a highly lethal malignancy in which relatively modest therapeutic advances have been made over the past several decades. Cytotoxic therapy remains the mainstay of treatment for both advanced esophageal adenocarcinoma and squamous cell carcinoma (SCC), with incremental benefit conferred by antibodies targeting HER2 and VEGFR in selected patients. However, intrinsic or acquired resistance in this disease almost invariably occurs and remains a major challenge. Moreover, although large-scale exome and whole-genome sequencing efforts have identified a variety of somatic mutations and copy number variations, particularly amplifications, in esophageal cancer, the ability to translate these findings successfully into actionable therapeutic approaches has been elusive. More recently, immunotherapeutic strategies, most notably immune checkpoint inhibitors, have demonstrated benefit to a subset of patients with both esophageal adenocarcinoma and SCC and represent an area of active clinical investigation. In this article, we discuss some of the insights derived from past trials of esophageal cancer, highlight ongoing research efforts in this arena, and emphasize the need to refine our approach to treating patients based on distinct anatomic, histologic, and molecular features.
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