ERBB receptors were linked to human cancer pathogenesis approximately three decades ago. Biomedical investigators have since developed substantial understanding of the biology underlying the ...dependence of cancers on aberrant ERBB receptor signaling. An array of cancer-associated genetic alterations in ERBB receptors has also been identified. These findings have led to the discovery and development of mechanism-based therapies targeting ERBB receptors that have improved outcome for many cancer patients. In this Perspective, we discuss current paradigms of targeting ERBB receptors with cancer therapeutics and our understanding of mechanisms of action and resistance to these drugs. As current strategies still have limitations, we also discuss challenges and opportunities that lie ahead as basic scientists and clinical investigators work toward more breakthroughs.
Estrogen receptor-positive (ER+) breast cancer is the most common breast cancer subtype. Treatment of ER+ breast cancer comprises interventions that suppress estrogen production and/or target the ER ...directly (overall labeled as endocrine therapy). While endocrine therapy has considerably reduced recurrence and mortality from breast cancer, de novo and acquired resistance to this treatment remains a major challenge. An increasing number of mechanisms of endocrine resistance have been reported, including somatic alterations, epigenetic changes, and changes in the tumor microenvironment. Here, we review recent advances in delineating mechanisms of resistance to endocrine therapies and potential strategies to overcome such resistance.
Estrogen receptor-positive (ER+) breast cancer is the most common breast cancer subtype. Treatment of ER+ breast cancer comprises interventions that suppress estrogen production and/or target the ER directly (overall labeled as endocrine therapy). While endocrine therapy has considerably reduced recurrence and mortality from breast cancer, de novo and acquired resistance to this treatment remains a major challenge. An increasing number of mechanisms of endocrine resistance have been reported, including somatic alterations, epigenetic changes, and changes in the tumor microenvironment. Here, we review recent advances in delineating mechanisms of resistance to endocrine therapies and potential strategies to overcome such resistance.
Anticancer targeted therapies are designed to exploit a particular vulnerability in the tumor, which in most cases results from its dependence on an oncogene and/or loss of a tumor suppressor. Genes ...in the phosphoinositide 3-kinase (PI3K)/AKT pathway are the most frequently altered in human cancers. Aberrant activation of this pathway, as a result of these somatic alterations, is associated with cellular transformation, tumorigenesis, cancer progression, and drug resistance. Several drugs targeting PI3K/ATK are currently in clinical trials, alone or in combination, in both solid tumors and hematologic malignancies. These drugs are the focus of this review.
Anti-cancer cancer-targeted therapies are designed to exploit a particular vulnerability in the tumor, which in most cases results from its dependence on an oncogene and/or loss of a tumor ...suppressor. Mutations in the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway are freqcuently found in breast cancers and associated with cellular transformation, tumorigenesis, cancer progression, and drug resistance. Several drugs targeting PI3K/ATK/mTOR are currently in clinical trials, mainly in combination with endocrine therapy and anti-HER2 therapy. These drugs are the focus of this review.
Although antiestrogen therapies targeting estrogen receptor (ER) α signaling prevent disease recurrence in the majority of patients with hormone-dependent breast cancer, a significant fraction of ...patients exhibit de novo or acquired resistance. Currently, the only accepted mechanism linked with endocrine resistance is amplification or overexpression of the ERBB2 (human epidermal growth factor receptor 2 HER2) proto-oncogene. Experimental and clinical evidence suggests that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway, the most frequently mutated pathway in breast cancer, promotes antiestrogen resistance. PI3K is a major signaling hub downstream of HER2 and other receptor tyrosine kinases. PI3K activates several molecules involved in cell-cycle progression and survival, and in ER-positive breast cancer cells, it promotes estrogen-dependent and -independent ER transcriptional activity. Preclinical tumor models of antiestrogen-resistant breast cancer often remain sensitive to estrogens and PI3K inhibition, suggesting that simultaneous targeting of the PI3K and ER pathways may be most effective. Herein, we review alterations in the PI3K pathway associated with resistance to endocrine therapy, the state of clinical development of PI3K inhibitors, and strategies for the clinical investigation of such drugs in hormone receptor-positive breast cancer.
The PI3K pathway is mutated and aberrantly activated in many cancers and plays a central role in tumor cell proliferation and survival, making it a rational therapeutic target. Until recently, ...however, results from clinical trials with PI3K inhibitors in solid tumors have been largely disappointing. Here, we describe several factors that have limited the success of these agents, including the weak driver oncogenic activity of mutant PI3K, suboptimal patient selection in trials, drug-related toxicities, feedback upregulation of compensatory mechanisms when PI3K is blocked, increased insulin production upon PI3Kα inhibition, lack of mutant-specific inhibitors, and a relative scarcity of studies using combinations with PI3K antagonists. We also suggest strategies to improve the impact of these agents in solid tumors. Despite these challenges, we are optimistic that isoform-specific PI3K inhibitors, particularly in combination with other agents, may be valuable in treating appropriately selected patients with PI3K-dependent tumors. SIGNIFICANCE: Despite the modest clinical activity of PI3K inhibitors in solid tumors, there is an increasing understanding of the factors that may have limited their success. Strategies to ameliorate drug-related toxicities, use of rational combinations with PI3K antagonists, development of mutant-selective PI3K inhibitors, and better patient selection should improve the success of these targeted agents against solid tumors.
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB receptor family that is abnormally activated in many epithelial tumors. The aberrant activation of the EGFR leads ...to enhanced proliferation and other tumor-promoting activities, which provide a strong rationale to target this receptor family. There are two classes of anti-EGFR agents: monoclonal antibodies (MAbs) directed at the extracellular domain of the receptor and small molecule, adenosine triphosphate-competitive inhibitors of the receptor's tyrosine kinase. Anti-EGFR MAbs have shown antitumor activity in advanced colorectal carcinoma, squamous cell carcinomas of the head and neck, non-small-cell lung cancer (NSCLC) and renal cell carcinomas. The tyrosine kinase inhibitors (TKIs) have a partially different activity profile. They are active against NSCLC, and a specific EGFR inhibitor has shown improvement in survival. Recently, mutations and amplifications of the EGFR gene have been identified in NSCLC and predict for enhanced sensitivity to anti-EGFR TKIs. In addition to specific anti-EGFR TKIs, there are broader acting inhibitors such as dual EGFR HER-2 inhibitors and combined anti-pan-ErbB and antivascular endothelial growth factor receptor inhibitors. Current research efforts are directed at selecting the optimal dose and schedule and identifying predictive factors of response and resistance beyond EGFR gene mutations and/or amplifications. Finally, there is a need for improved strategies to integrate anti-EGFR agents with conventional therapies and to explore combinations with other molecular targeted approaches including other antireceptor therapies, receptor-downstream signaling transduction inhibitors, and targeted approaches interfering with other essential drivers of cancer, such as angiogenesis.
Most patients with advanced triple-negative breast cancer (TNBC) develop drug resistance. MYC and MCL1 are frequently co-amplified in drug-resistant TNBC after neoadjuvant chemotherapy. Herein, we ...demonstrate that MYC and MCL1 cooperate in the maintenance of chemotherapy-resistant cancer stem cells (CSCs) in TNBC. MYC and MCL1 increased mitochondrial oxidative phosphorylation (mtOXPHOS) and the generation of reactive oxygen species (ROS), processes involved in maintenance of CSCs. A mutant of MCL1 that cannot localize in mitochondria reduced mtOXPHOS, ROS levels, and drug-resistant CSCs without affecting the anti-apoptotic function of MCL1. Increased levels of ROS, a by-product of activated mtOXPHOS, led to the accumulation of HIF-1α. Pharmacological inhibition of HIF-1α attenuated CSC enrichment and tumor initiation in vivo. These data suggest that (1) MYC and MCL1 confer resistance to chemotherapy by expanding CSCs via mtOXPHOS and (2) targeting mitochondrial respiration and HIF-1α may reverse chemotherapy resistance in TNBC.
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•MYC and MCL1 increase cancer stem cells in chemotherapy-resistant TNBC•MYC and MCL1 cooperatively promote mtOXPHOS, which in turn induces HIF-1α•MCL1 induces CSCs independent of its BH3-dependent, anti-apoptotic function•Inhibition of HIF1-α abolishes CSC enrichment in chemotherapy-resistant TNBC
MYC and MCL1 are co-amplified in drug-resistant breast cancer. Lee et al. reveal that MYC and MCL1 cooperate to maintain cancer stem cells (CSCs) resistant to chemotherapy by increasing mitochondrial OXPHOS, ROS production, and HIF-1α expression. Inhibition of HIF-1α blocks CSC expansion and restores chemotherapy sensitivity.
Mutations in genes that constitute the phosphatidylinositol 3-kinase (PI3K) pathway occur in >70% of breast cancers. Clinical and experimental evidence suggest that PI3K pathway activation promotes ...resistance to some of the current breast cancer therapies. PI3K is a major signaling hub downstream of human epidermal growth factor receptor (HER)2 and other receptor tyrosine kinases. PI3K activates AKT, serum/glucocorticoid regulated kinase (SGK), phosphoinositide-dependent kinase 1 (PDK1), mammalian target of rapamycin (mTOR), and several other molecules involved in cell cycle progression and survival. In estrogen receptor (ER)+ breast cancer cells, PI3K activation promotes estrogen-dependent and -independent ER transcriptional activity, which, in turn, may contribute to anti-estrogen resistance. Activation of this pathway also confers resistance to HER2-targeted therapies. In experimental models of resistance to anti-estrogens and HER2 inhibitors, pharmacological inhibition of PI3K/AKT/mTOR has been shown to overcome drug resistance. Early clinical data suggest that combined inhibition of either HER2 or ER plus inhibition of the PI3K pathway might be an effective strategy for treatment of respective HER2+ and ER+ breast cancers resistant to standard therapies. Here, we review alterations in the PI3K pathway in breast cancer, their association with therapeutic resistance, and the state of clinical development of PI3K pathway inhibitors.
We examined the effects of an inhibitor of PI3K, XL147, against human breast cancer cell lines with constitutive PI3K activation. Treatment with XL147 resulted in dose-dependent inhibition of cell ...growth and levels of pAKT and pS6, signal transducers in the PI3K/AKT/TOR pathway. In HER2-overexpressing cells, inhibition of PI3K was followed by up-regulation of expression and phosphorylation of multiple receptor tyrosine kinases, including HER3. Knockdown of FoxO1 and FoxO3a transcription factors suppressed the induction of HER3, InsR, IGF1R, and FGFR2 mRNAs upon inhibition of PI3K. In HER2+ cells, knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitors trastuzumab or lapatinib enhanced XL147-induced cell death and inhibition of pAKT and pS6. Trastuzumab and lapatinib each synergized with XL147 for inhibition of pAKT and growth of established BT474 xenografts. These data suggest that PI3K antagonists will inhibit AKT and relieve suppression of receptor tyrosine kinase expression and their activity. Relief of this feedback limits the sustained inhibition of the PI3K/AKT pathway and attenuates the response to these agents. As a result, PI3K pathway inhibitors may have limited clinical activity overall if used as single agents. In patients with HER2-overexpressing breast cancer, PI3K inhibitors should be used in combination with HER2/HER3 antagonists.
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