ABCDEFGHIJK
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FactorDirectly InfluencesIndirectly InfluencesCommentsTreatment TypeTreatmentMechanismEffectTreatment CommentCommon Side EffectsRare (Serious) Side Effects
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EGFR Mutation
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exon 19 deletions, L858R, mutationsMutant EGFR protein that lacks a portion of its extracellular domain and has a constitutively active tyrosine kinase domain.Tumor Microenvironment, Immune Evasion, AngiogenesisDriver mutations initiate and sustain cancer growth.Tyrosine Kinase Inhibitors (TKIs):Erlotinib (Tarceva): 1st genBinds reversibly to the ATP-binding site of the EGFR tyrosine kinase domain, inhibiting its activity.Blocks downstream signaling pathways that promote cell proliferation and survival, leading to cell cycle arrest and apoptosis in EGFR-mutant cancer cells.
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Driver mutations initiate and sustain cancer growth.Gefitinib (Iressa): 1st genSimilar to ErlotinibSimilar to ErlotinibThis is similar to Erlotinib but has less drug interactions, and work on a broader specttrum
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Driver mutations initiate and sustain cancer growth.Afatinib (Gilotrif): 2nd genIrreversibly binds to the EGFR tyrosine kinase domain as well as other members of the ErbB family (HER2, HER4).Provides a more comprehensive inhibition of EGFR and related receptors, leading to sustained suppression of tumor growth.diarrhea, rash, stomatitis, and paronychia
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Driver mutations initiate and sustain cancer growth.Dacomitinib (Vizimpro): 2nd genAlso an irreversible binder of the EGFR tyrosine kinase domain, targeting multiple ErbB family members.Offers prolonged inhibition of the EGFR signaling pathway, overcoming some forms of resistance seen with first-generation TKIs.Dacomitinib offers slightlyimproved better progression-free survival compared to Afatinib,diarrhea, rash, stomatitis, and paronychia
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T790M resistance mutationT790M mutant EGFR still retains some ATP-binding capability. This allows the receptor to maintain a basal level of activity, sufficient to drive cancer cell survival and proliferation.Osimertinib (Tagrisso): 3rd genIrreversibly binds to the ATP-binding site of the EGFR tyrosine kinase domain, specifically targeting both the sensitizing mutations (e.g., exon 19 deletions, L858R) and the T790M resistance mutation.Effective against cancers that have developed resistance to first- and second-generation TKIs, with better central nervous system penetration, making it useful for treating brain metastases.diarrhea, rash, dry skin, nail changes, fatigue, decreased appetite, stomatitis, cough, nauseaInterstitial Lung Disease (ILD), QT Prolongation, Cardiomyopathy, Keratitis, Hepatotoxicity
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ALK, ROS1Driver mutations initiate and sustain cancer growth.CrizotinibCrizotinib is a tyrosine kinase inhibitor (TKI) that targets and inhibits the activity of ALK and ROS1 protein kinases. It binds to the ATP-binding site of ALK and ROS1, preventing their phosphorylation and subsequent activation of downstream signaling pathways. It has shown significant efficacy in shrinking tumors and improving progression-free survival in patients with these specific genetic alterations.Nausea, Vomiting, Diarrea, constipation, Blurred vision, Photopsia, swelling of hands, feet,Interstitial lung disease (ILD), QT Prolongation, Cardiomyopathy, Keratitis, Hepatotoxicity
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ALKCeritinibIt binds to the ATP-binding site of ALK kinase, thereby inhibiting its phosphorylation (activation) and subsequent downstream signaling pathways.By inhibiting ALK signaling, ceritinib disrupts several oncogenic pathways that are crucial for cancer cell proliferation and survival, including the RAS-RAF-MEK-ERK and PI3K-AKT-mTOR pathways.CNS Activity: Ceritinib has shown the ability to penetrate the blood-brain barrier, allowing it to target ALK-positive metastases in the central nervous system (CNS).nausea, diarrhea, vomiting,Fatigue, swellingIDL, QT
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ALKAlectinibIt binds to the ATP-binding site of ALK, inhibiting its phosphorylation and subsequent activation.Alectinib has demonstrated efficacy against various ALK mutations, including those that confer resistance to first-generation ALK inhibitors like Crizotinib (e.g., L1196M mutation).It has shown superior efficacy compared to Crizotinib in terms of progression-free survival and overall response rates in clinical trials.Nausea, Vomiting, Diarrea, constipation, Blurred vision, Photopsia, swelling of hands, feet,Interstitial lung disease (ILD), QT Prolongation, Cardiomyopathy, Keratitis, Hepatotoxicity
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ALK, ROS1 Lorlatinib (3rd Gen)It binds to the ATP-binding site of ALK and ROS1, inhibiting their phosphorylation and subsequent activation.reatment of ALK-positive metastatic NSCLC in patients who have progressed on Crizotinib and at least one other ALK inhibitor, or those who are intolerant to prior therapy.It has demonstrated high response rates and durable responses in patients with ALK-positive NSCLC, including those with CNS metastases.Cognitive effects (memory impairment, confusion), Mood changes (depression, anxiety),Nausea, Vomiting, Diarrea, constipation, Blurred vision, Photopsia, swelling of hands, feet,
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KRAS G12CSotorasibbinds irreversibly to the mutated KRAS protein, locking it in an inactive state.By inhibiting KRAS G12C, sotorasib disrupts signaling pathways involved in cell growth and survival, thereby inhibiting tumor growth.
Sotorasib is the first approved therapy that directly targets the KRAS G12C mutation, which is commonly found in NSCLC and other cancers such as colorectal cancer.Nausea, Vomiting, Diarrea, constipation
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KRAS G12CAdagrasib It binds irreversibly to the mutated KRAS G12C protein, locking it in an inactive GDP-bound stateAdagrasib selectively binds to the KRAS G12C mutation without affecting the wild-type KRAS protein, minimizing off-target effects.
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Tumor Suppressor Gene Loss (e.g., TP53)APR-246APR-246 binds to mutant p53 and induces a conformational change, restoring its wild-type function.APR-246 also interacts with glutathione, leading to increased levels of reactive oxygen species (ROS) and oxidative stress within cancer cells. This oxidative stress contributes to the induction of apoptosis in tumor cells.
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Tumor Microenvironment (CAFs, TAMs, MDSCs)
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hyaluronan (HA) accumulation, (Adenocarcinoma, Large Cell Carcinoma) degrade hyaluronan (HA), a large glycosaminoglycan component of the extracellular matrix (ECM) that contributes to increased interstitial fluid pressure in tumors.PEGPH20 degrades HABy degrading HA, PEGPH20 can potentially improve drug delivery to tumor cells, enhance immune cell infiltration, and reduce the mechanical barriers that impede therapeutic efficacy.
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 CSF-1R CSF-1R InhibitorsCSF-1R inhibitors can deplete or reprogram TAMs, shifting their phenotype from a pro-tumorigenic (M2-like) to an anti-tumorigenic (M1-like) state. In addition to TAM modulation, CSF-1R inhibitors may have direct effects on tumor cells themselves, including inhibition of proliferation and survival pathways.By targeting TAMs and potentially directly affecting tumor cells, CSF-1R inhibitors aim to inhibit tumor growth, reduce metastasis, and enhance the effectiveness of other anticancer therapies.
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interleukin-2 receptor alpha chain (CD25) Tregs They inhibit the activation and proliferation of effector T cells, which are responsible for recognizing and attacking cancer cells. Elevated numbers of Tregs expressing CD25 in the tumor microenvironment contribute to immune evasion by suppressing antitumor immune responses.Anti-CD25 Antibodies Anti-CD25 antibodies bind to CD25 on Tregs, leading to their depletion or modulation of their function. Tregs suppress the immune response against tumor cells, so reducing their numbers or activity can enhance antitumor immunity.
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Hypoxia (HIF-1α Activation)
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HIF-1αAdaptation to hypoxia, such as those promoting angiogenesis, glycolysis, and cell survivalPX-478inhibits the expression and activity of HIF-1α, thereby disrupting these adaptive responses of cancer cells to low oxygen levels.By inhibiting HIF-1α, PX-478 aims to suppress tumor growth and metastasis, reduce angiogenesis (formation of new blood vessels), and sensitize cancer cells to radiation and chemotherapy.
It may induce apoptosis (programmed cell death) in cancer cells under hypoxic conditions.
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hypoxiaHypoxia induces the stabilization and activation of HIFs, especially HIF-1α and HIF-2α, which are transcription factors that regulate the expression of genes involved in adaptation to low oxygen conditions. These genes promote angiogenesis (formation of new blood vessels), glycolysis (a form of energy production), cell survival, and metastasis—all of which contribute to tumor growth and progression.Hypoxia stimulates the secretion of angiogenic factors such as vascular endothelial growth factor (VEGF), which promotes the formation of new blood vessels. Increased angiogenesis helps tumors maintain adequate blood supply, allowing them to grow and metastasize more effectively.TH-302 (evofosfamide)TH-302 is a prodrug that is selectively activated under hypoxic conditions, which are prevalent in many solid tumors, including lung cancer.In the low oxygen environment of tumors, TH-302 undergoes chemical activation to release a DNA-crosslinking agent, bromo-isophosphoramide mustard (Br-IPM), directly within the hypoxic cells. Once activated, Br-IPM induces DNA crosslinking and breaks, leading to cytotoxicity and cell death specifically within the hypoxic tumor regions.
This targeted cytotoxic effect aims to reduce tumor growth and improve treatment outcomes.
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Immune Checkpoints (PD-L1, CTLA-4)
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PD-1/PD-L1PD-1 is a checkpoint protein that, when bound to its ligands PD-L1 or PD-L2 (expressed on tumor cells and immune cells), inhibits T cell activity and prevents immune responses against cancer cells.Nivolumab (Opdivo)Targets the PD-1 receptor on T cells, preventing its interaction with PD-L1 and PD-L2 ligands expressed on tumor cells and immune cells.Nivolumab enhances the immune response against lung cancer cells by releasing the inhibition on T cells, allowing them to target and kill cancer cells more effectively.
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Pembrolizumab (Keytruda)
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PD-L1/PD-1Atezolizumab Targets the PD-L1 ligand itself, blocking its interaction with PD-1 on T cells and B7-1 on antigen-presenting cells.enhanced Antitumor Immunity: Atezolizumab enhances the immune response against lung cancer cells, leading to tumor shrinkage and potentially prolonged disease control.
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CTLA-4CTLA-4 competes with the co-stimulatory molecule CD28 for binding to B7 ligands (CD80 and CD86) on antigen-presenting cells (APCs)When CTLA-4 binds to B7 ligands, it inhibits T cell activation and suppresses immune responses against cancer cells.Ipilimumab Binds to CTLA-4 directly. By blocking CTLA-4, ipilimumab enhances T cell activation and promotes immune responses against tumors, including lung cancer.Ipilimumab enhances the immune response against lung cancer cells by releasing the inhibition on T cells, leading to increased tumor cell killing.
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Immunosuppressive Molecules (TGF-β, IL-10)is a key regulator of EMT. metastasis
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TGF-βTGF-β signaling can promote tumor progression by stimulating cell proliferation, angiogenesis (formation of new blood vessels), and immune evasion. Fresolimumab aims to block these pathways.GalunisertibGalunisertib inhibits the TGF-β receptor type I (ALK5), which is involved in mediating downstream signaling of TGF-β.TGF-β is a multifunctional cytokine that promotes tumor progression by regulating processes such as cell proliferation, differentiation, migration, and immune suppression.
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TGF-β1, TGF-β2, and TGF-β3Fresolimumab Fresolimumab is a monoclonal antibody that binds to and neutralizes all isoforms of TGF-β (TGF-β1, TGF-β2, and TGF-β3).
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IL-10IL-10 is involved in suppressing immune responses by inhibiting the production of pro-inflammatory cytokines and reducing antigen presentation by antigen-presenting cells (APCs).Anti-IL-10 AntibodiesAnti-IL-10 antibodies specifically bind to IL-10, preventing it from interacting with its receptors on immune cells.Blocking IL-10 can lead to increased activation and function of cytotoxic T cells, natural killer (NK) cells, and other immune effector cells against tumor cells.
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Metabolic Competition (Glucose, Amino Acid Deprivation)
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Warburg effectMetabolize glucose (glycolysis) even in the presence of oxygenMetformin Metformin primarily works by decreasing glucose production in the liver and increasing insulin sensitivity in peripheral tissues (muscle and fat).
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LDH LDH is an enzyme involved in the conversion of pyruvate to lactate during anaerobic glycolysis, a process that cancer cells often rely on for energy production, even in the presence of oxygen (Warburg effect).LDH InhibitorsLDH inhibitors work by blocking the activity of LDH, thereby reducing the conversion of pyruvate to lactate.By inhibiting LDH, these compounds aim to disrupt cancer cell metabolism, potentially leading to decreased cell proliferation and survival.
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Physical Barriers (Dense ECM, Fibrotic Stroma)
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Collagen fibersIncreased collagenase activity may promote tumor cell invasion by facilitating their movement through the ECM.Collagenase Collagenase enzymes target and break down collagen fibers within the ECM of tissues. In cancer, including lung cancer, alterations in the ECM can contribute to tumor progression, invasion, and metastasis.
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FibrosisFibrotic tissue can provide a reservoir of growth factors and cytokines that stimulate tumor cell proliferation and survival. t can also facilitate angiogenesis (formation of new blood vessels), which supports tumor growth by providing nutrients and oxygen to cancer cells.Pirfenidone TGF-β: Reduces TGF-β levels, which is a key cytokine involved in fibrosis and cancer progression.
PDGF (Platelet-Derived Growth Factor): Inhibits PDGF-induced proliferation of fibroblasts.
TNF-α (Tumor Necrosis Factor-alpha): Reduces production of TNF-α, which is involved in inflammation and fibrosis.
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Angiogenesis (VEGF Pathway)
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 VEGF-Apromoting angiogenesis, which is the formation of new blood vessels from pre-existing ones. Here’s how VEGF contributes to lung cancer progression:The dense network of blood vessels formed due to VEGF-induced angiogenesis can create physical barriers that limit the penetration and effectiveness of chemotherapy drugs and immune cells into the tumor.Bevacizumab Bevacizumab binds to VEGF-A, a major isoform of VEGF, preventing it from interacting with its receptors (VEGFRs) on endothelial cells.By blocking VEGF-A, bevacizumab inhibits the signaling pathways that promote angiogenesis, thereby reducing the formation of new blood vessels around tumors (anti-angiogenic effect).
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RTKs, VEGFR, PDGFR, KIT, RETsignaling pathways that promote tumor growth, angiogenesis, and metastasis.Sunitinib Sunitinib inhibits VEGFRs, reducing the formation of new blood vessels around tumors and thereby limiting their blood supply.It may directly inhibit tumor cell proliferation and survival by targeting specific RTKs that are overactive in cancer cells.
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VEGF ThalidomideThalidomide inhibits angiogenesis, the formation of new blood vessels, by suppressing the production of VEGF and other pro-angiogenic factors.
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VEGF Lenalidomide Lenalidomide modulates immune responses by enhancing the activity of T cells and natural killer (NK) cells, which are important for immune surveillance against cancer cells.Similar to thalidomide, lenalidomide exhibits anti-angiogenic properties by inhibiting the production of VEGF and other pro-angiogenic factors.
This action helps in reducing the formation of new blood vessels around tumors, potentially limiting their blood supply and growth.
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Metastasis (EMT, CTCs)
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Wntis involved in regulating stem cell self-renewal and differentiation.Salinomycin Salinomycin inhibits the Wnt signaling pathway, which is involved in regulating stem cell self-renewal and differentiation.By disrupting Wnt signaling, salinomycin can induce differentiation of CSCs and inhibit their ability to regenerate tumors.
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Therapy Resistance (Drug Efflux Pumps, Resistant Clones)
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P-glycoprotein (Drug Efflux Pumps) which is a drug efflux pump present in cell membranes. P-gp plays a role in pumping drugs out of cells, thereby reducing their intracellular concentration and potentially decreasing their efficacy.Tariquidar Tariquidar inhibits P-glycoproteinBy inhibiting P-gp, tariquidar can increase the intracellular concentration and enhance the effectiveness of certain chemotherapy drugs that are substrates for P-gp. This mechanism is particularly relevant in overcoming multidrug resistance in cancer cells, where P-gp overexpression can contribute to treatment resistance.
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P-glycoprotein (Drug Efflux Pumps)Ivermectin
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Other Therapies
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CAR-T cell therapy
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