Mechanisms of tumor resistance to EGFR-targeted therapies

Hopper-Borge, Elizabeth; Nasto, Rochelle E.; Ratushny, Vladimir; Weiner, Louis M.; Golemis, Erica A.; Astsaturov, Igor

doi:10.1517/14712590902735795

Cited by 85 publications

(46 citation statements)

References 221 publications

(261 reference statements)

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“…In such a scenario, fitness of a cancer cell is determined by the robustness of its signaling network as a whole. The resistance-mediating genes that we have identified should undergo scrutiny as alternative EGFR modulators, joining with proteins such as KRAS, BRAF (a MAPKKK), c-MET (a receptor tyrosine kinase), IGF1 (insulin growth factor 1), and others (36). …”

Section: Discussionmentioning

confidence: 99%

Synthetic Lethal Screen of an EGFR-Centered Network to Improve Targeted Therapies

et al. 2010

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Intrinsic and acquired cellular resistance factors limit the efficacy of most targeted cancer therapeutics. Synthetic lethal screens in lower eukaryotes suggest that networks of genes closely linked to therapeutic targets would be enriched for determinants of drug resistance. We developed a protein network centered on the epidermal growth factor receptor (EGFR), which is a validated cancer therapeutic target, and used siRNA screening to comparatively probe this network for proteins that regulate the effectiveness of both EGFR-targeted agents and nonspecific cytotoxic agents. We identified subnetworks of proteins influencing resistance, with putative resistance determinants enriched among proteins that interacted with proteins at the core of the network. We found that EGFR antagonists and clinically relevant drugs targeting proteins connected in the EGFR network, such as the kinases protein kinase C or Aurora kinase A, or the transcriptional regulator STAT3, synergized to reduce cell viability and tumor size, suggesting the potential for a direct path to clinical exploitation. Such a focused approach can potentially improve the coherent design of combination cancer therapies.

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Section: Discussionmentioning

confidence: 99%

Synthetic Lethal Screen of an EGFR-Centered Network to Improve Targeted Therapies

et al. 2010

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“…70,[179][180][181] Clinically, patients with EGFR exon 20 mutations do not respond to gefitinib. 67 Moreover, the appearance of a secondary mutation in exon 20 (T790M) accounts for B50% of acquired drug resistance.…”

Section: Mechanisms Of Resistance To Egfr Targeted Therapymentioning

confidence: 99%

Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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The majority of lung adenocarcinoma patients with epidermal growth factor receptor-(EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

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“…Various mechanisms including mutations, activation of multidrug transporters, and overexpression or activation of signaling proteins are operating as exemplified for EGFR-targeted therapies. 46 Another major problem is poor penetration into tissues, e.g., solid tumors. A related issue for full-size mAbs is poor or absent binding to regions on the surface of some molecules, i.e., existence of "steric barriers," e.g., on the HIV envelope glycoprotein (Env).…”

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confidence: 99%

Therapeutic antibodies, vaccines and antibodyomes

Dimitrov

2010

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T he potential for antibodies to act as "magic bullets" for treatment of human disease was recognized a century ago, but its full realization has began to occur only during the last decade. A key to their current success is the ability to make libraries of antibodies/B cells, isolate a single species, and engineer it to be safe, efficacious and of high quality. Despite this progress, major challenges to the effective prevention, diagnosis and treatment of a vast majority of diseases remain. Limited success in the development of effective vaccines against diseases such as AIDS and cancer reflects our incomplete understanding of how antibodies are generated and function. Only a miniscule number of antibodies are characterized out of the universe of antibodies generated by the immune system. Knowledge of antibodyomes-the complete sets of antibodies-could help solve these and other challenges.

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Mechanisms of tumor resistance to EGFR-targeted therapies

Cited by 85 publications

References 221 publications

Synthetic Lethal Screen of an EGFR-Centered Network to Improve Targeted Therapies

Synthetic Lethal Screen of an EGFR-Centered Network to Improve Targeted Therapies

Molecular pathology of lung cancer: key to personalized medicine

Therapeutic antibodies, vaccines and antibodyomes

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