Protein kinases regulate nearly all aspects of cell life, and alterations in their expression, or mutations in their genes, cause cancer and other diseases. Here, we review the remarkable progress ...made over the past 20 years in improving the potency and specificity of small-molecule inhibitors of protein and lipid kinases, resulting in the approval of more than 70 new drugs since imatinib was approved in 2001. These compounds have had a significant impact on the way in which we now treat cancers and non-cancerous conditions. We discuss how the challenge of drug resistance to kinase inhibitors is being met and the future of kinase drug discovery.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
All patients with metastatic lung, colorectal, pancreatic or head and neck cancers who initially benefit from epidermal growth factor receptor (EGFR)-targeted therapies eventually develop resistance. ...An increasing understanding of the number and complexity of resistance mechanisms highlights the Herculean challenge of killing tumors that are resistant to EGFR inhibitors. Our growing knowledge of resistance pathways provides an opportunity to develop new mechanism-based inhibitors and combination therapies to prevent or overcome therapeutic resistance in tumors. We present a comprehensive review of resistance pathways to EGFR-targeted therapies in lung, colorectal and head and neck cancers and discuss therapeutic strategies that are designed to circumvent resistance.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase ...inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A multicenter phase 2 study looked at the capacity of the antibody–drug conjugate trastuzumab deruxtecan to induce responses in
HER2
-mutant lung cancer. The response rate was 55%, with median ...progression-free survival of 8.2 months. Potentially serious interstitial lung disease developed in approximately 1 patient in 4.
The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop ...drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Plasma cell-free DNA (cfDNA) genotyping is increasingly used in cancer care, but assay accuracy is debated. Because most cfDNA is derived from peripheral blood cells (PBC), we hypothesized that ...nonmalignant mutations harbored by hematopoietic cells (clonal hematopoiesis, CH) could be a cause of false positive plasma genotyping. Experimental Design: We identified patients with advanced NSCLC with
,
, or
mutations identified in cfDNA. With consent, PBC DNA was tested using droplet digital PCR (ddPCR) or next-generation sequencing (NGS) to test for CH-derived mutations. Results: We first studied plasma ddPCR results from 58
-mutant NSCLC patients. Two had
G12X detected in cfDNA and both were present in PBC, including one where the
mutation was detected serially for 20 months. We then studied 143 plasma NGS results from 122 NSCLC patients, and identified 5
V617F mutations derived from PBC. Additionally, 108
mutations were detected in cfDNA; for 33 of the
mutations, PBC and tumor NGS were available for comparison, and 5 were present in PBC but absent in tumor, consistent with CH.
We find that most
mutations, some
mutations, and rare
mutations detected in cfDNA are derived from CH not tumor. Clinicians ordering plasma genotyping must be prepared for the possibility that mutations detected in plasma, particularly in genes mutated in CH, may not represent true tumor genotype. Efforts to use plasma genotyping for cancer detection may need paired PBC genotyping so that CH-derived mutations are not misdiagnosed as occult malignancy.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib are effective therapies for non–small
cell lung cancer patients whose tumors harbor somatic mutations in ...EGFR . All patients, however, ultimately develop resistance to these agents. Thus, there is a great need to understand how patients
become resistant to develop effective therapies for these cancers. Studies over the last few years have identified two different
EGFR tyrosine kinase inhibitor resistance mechanisms, a secondary mutation in EGFR, EGFR 790M, and amplification of the MET oncogene. These findings have led to clinical trials using newly designed targeted therapies that can overcome these resistance
mechanisms and have shown promise in laboratory studies. Ongoing research efforts will likely continue to identify additional
resistance mechanisms, and these findings will hopefully translate into effective therapies for non–small cell lung cancer
patients.
Abstract The fusion between echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) has recently been identified in a subset of non-small cell lung cancers ...(NSCLCs). EML4-ALK is most often detected in never smokers with lung cancer and has unique pathologic features. EML4-ALK is oncogenic both in vitro and in vivo and ALK kinase inhibitors are quite effective in pre-clinical model systems. More recently ALK inhibitors have entered clinical development and remarkably clinical efficacy has been observed in NSCLC patients harbouring EML4-ALK translocations. This review will focus on the biology, clinical characteristics, diagnosis and treatment of EML4-ALK NSCLC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Tyrosine kinase inhibitors (TKIs) have dramatically changed the clinical prospects of patients with non-small cell lung cancer harboring epidermal growth factor receptor (EGFR)-activating mutations. ...Despite prolonged disease control and high tumor response rates, all patients eventually progress on EGFR TKI treatment. Here, we review the mechanisms of acquired EGFR TKI resistance, the methods for monitoring its appearance, as well as current and future efforts to define treatment strategies to overcome resistance.
HER3 is a pseudokinase member of the EGFR family having a role in both tumor progression and drug resistance. Although HER3 was discovered more than 30 years ago, no therapeutic interventions have ...reached clinical approval to date. Because the evidence of the importance of HER3 is accumulating, increased amounts of preclinical and clinical trials with HER3-targeting agents are emerging. In this review article, we discuss the most recent HER3 biology in tumorigenic events and drug resistance and provide an overview of the current and emerging strategies to target HER3.
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