AKT Inhibitor Ipatasertib in Metastatic Triple-Negative Breast Cancer

Excerpt:

“The randomized phase II LOTUS trial has shown improved progression-free survival with the addition of the AKT inhibitor ipatasertib to paclitaxel in the first-line treatment of metastatic triple-negative breast cancer. These results were reported by Kim et al in The Lancet Oncology. The PI3K/AKT signaling pathway is frequently activated in triple-negative breast cancer.

“In the double-blind trial, 124 patients with unresectable locally advanced or metastatic disease from 44 sites in South Korea, the United States, France, Spain, Taiwan, Singapore, Italy, and Belgium were randomized between September 2014 and February 2016 to receive paclitaxel at 80 mg/m² on days 1, 8, and 15 with either ipatasertib at 400 mg (n = 62) or placebo (n = 62) once daily on days 1 to 21 every 28 days until disease progression or unacceptable toxicity. Stratification factors included tumor PTEN status as determined by immunohistochemistry; deficient expression of PTEN is associated with greater AKT pathway activation. The co-primary endpoints were progression-free survival in the intention-to-treat population and progression-free survival in the PTEN-low population.”

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Phosphoproteomic Characterization of DNA Damage Response in Melanoma Cells Following MEK/PI3K Dual Inhibition

“Growing evidence suggests that successful intervention in many human cancers will require combinations of therapeutic agents. Critical to this effort will be a detailed understanding of the crosstalk between signaling networks that modulate proliferation, cell death, drug sensitivity, and acquired resistance. Here we investigated DNA-damage signaling elicited by small-molecule inhibitors against MAP/ERK kinase (MEK) and PI3K in melanoma cells. This work, performed using cutting-edge mass spectrometry proteomics, uncovered a burst of signaling among proteins in the DNA-damage pathway upon initiation of the cell-death program by agents targeting the RAS–RAF–MEK and PI3K–AKT–mTOR pathways. These signals may prove important to the short- and long-term sensitivity of tumor cells to MEK- and PI3K-targeted therapies.”


Differential AKT Dependency Displayed by Mouse Models of BRAFV600E-Initiated Melanoma

“Malignant melanoma is frequently driven by mutational activation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) accompanied by silencing of the phosphatase and tensin homology (PTEN) tumor suppressor. Despite the implied importance of PI3K signaling in PTENNull melanomas, mutational activation of the gene encoding the catalytic subunit of PI3Kα (PIK3CA), is rarely detected. Since PTEN has both PI3-lipid phosphatase–dependent and –independent tumor suppressor activities, we investigated the contribution of PI3K signaling to BRAFV600E-induced melanomagenesis using mouse models, cultured melanoma cells, and PI3K pathway–targeted inhibitors. These experiments revealed that mutationally activated PIK3CAH1047R cooperates with BRAFV600E for melanomagenesis in mice. Moreover, pharmacological inhibition of PI3Ks prevented growth of BRAFV600E/PTENNull melanomas in vivo and in tissue culture. Combined inhibition of BRAFV600E and PI3K had more potent effects on the regression of established BRAFV600E/PTENNull melanomas and cultured melanoma cells than individual blockade of either pathway. Surprisingly, growth of BRAFV600E/PIK3CAH1047R melanomas was dependent on the protein kinase AKT; however, AKT inhibition had no effect on growth of BRAFV600E/PTENNull melanomas. These data indicate that PTEN silencing contributes a PI3K-dependent, but AKT-independent, function in melanomagenesis. Our findings enhance our knowledge of how BRAFV600E and PI3K signaling cooperate in melanomagenesis and provide preclinical validation for combined pathway–targeted inhibition of PI3K and BRAFV600E in the therapeutic management of BRAFV600E/PTENNull melanomas.”


Conjunctival Melanomas Harbor BRAF and NRAS Mutations

The mutation BRAFV600E is found in conjunctival melanoma at approximately the same frequency as in cutaneous melanoma. The presence of this mutation should make this rare type of melanoma eligible for treatment with the BRAF inhibitors vemurafenib and dabrafenib, which have significant antitumor activity in BRAF V600E–mutant cutaneous melanoma. However, there are no published data on the use of BRAF inhibitors in patients with conjunctival melanoma. This letter reports that treatment of a patient with metastatic conjunctival melanoma using vemurafenib did not halt disease progression and had to be discontinued.  This could be due to the previously described frequent loss of the tumor suppressor PTEN and consequent activation of the PI3K pathway in conjunctival melanoma, warranting further studies of combination treatment of these tumors with BRAF and PI3K or AKT inhibitors.


Navigating the Therapeutic Complexity of PI3K Pathway Inhibition in Melanoma

“Melanoma is entering into an era of combinatorial approaches to build upon recent clinical breakthroughs achieved by novel single-agent therapies. One of the leading targets to emerge from the growing understanding of the molecular pathogenesis, heterogeneity, and resistance mechanisms of melanomas is the phosphoinositide 3-kinase (PI3K)–AKT pathway. Multiple genetic and epigenetic aberrations that activate this pathway have been identified in melanomas de novo and in acquired resistance models. These developments have been paralleled by the establishment of models for preclinical testing and the availability of compounds that target various effectors in the pathway. Thus, in addition to having a strong rationale for targeting, the PI3K–AKT pathway presents an immediate clinical opportunity. However, the development of effective strategies against this pathway must overcome several key challenges, including optimizing patient selection, overcoming feedback loops, and pathway cross-talk that can mediate resistance. This review discusses the current understanding and ongoing research about the PI3K–AKT pathway in melanoma and emerging strategies to achieve clinical benefit in patients by targeting it.”


Associations between Single Nucleotide Polymorphisms in the PI3K/PTEN/AKT/mTOR Pathway and Increased Risk of Brain Metastasis in Patients with Non-Small-Cell Lung Cancer

The phosphatidylinositol-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) signaling pathway is important in the control of cell growth, tumorigenesis, and cell invasion. Genotype variants in this pathway could predict brain metastases (BM) in patients with NSCLC.

In analysis of individual SNPs, the GT/GG genotype of AKT1: rs2498804, CT/TT genotype of AKT1: rs2494732 and AG/AA genotype of PIK3CA: rs2699887 were associated with higher risk of BM at 24 months’ follow-up. These SNPs had a cumulative effect on BM risk, with that risk being highest for patients carrying both of these unfavorable genotypes.


Bypass Mechanisms of Resistance to Receptor Tyrosine Kinase Inhibition in Lung Cancer

“Receptor tyrosine kinases (RTKs) are activated by somatic genetic alterations in a subset of cancers, and such cancers are often sensitive to specific inhibitors of the activated kinase. Two well-established examples of this paradigm include lung cancers with either EGFR mutations or ALK translocations. In these cancers, inhibition of the corresponding RTK leads to suppression of key downstream signaling pathways, such as the PI3K (phosphatidylinositol 3-kinase)/AKT and MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal–regulated kinase) pathways, resulting in cell growth arrest and death. Despite the initial clinical efficacy of ALK (anaplastic lymphoma kinase) and EGFR (epidermal growth factor receptor) inhibitors in these cancers, resistance invariably develops, typically within 1 to 2 years. Over the past several years, multiple molecular mechanisms of resistance have been identified, and some common themes have emerged. One is the development of resistance mutations in the drug target that prevent the drug from effectively inhibiting the respective RTK. A second is activation of alternative RTKs that maintain the signaling of key downstream pathways despite sustained inhibition of the original drug target. Indeed, several different RTKs have been implicated in promoting resistance to EGFR and ALK inhibitors in both laboratory studies and patient samples. In this mini-review, we summarize the concepts underlying RTK-mediated resistance, the specific examples known to date, and the challenges of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.”


Bypass Mechanisms of Resistance to Receptor Tyrosine Kinase Inhibition in Lung Cancer

“Receptor tyrosine kinases (RTKs) are activated by somatic genetic alterations in a subset of cancers, and such cancers are often sensitive to specific inhibitors of the activated kinase. Two well-established examples of this paradigm include lung cancers with either EGFR mutations or ALK translocations. In these cancers, inhibition of the corresponding RTK leads to suppression of key downstream signaling pathways, such as the PI3K (phosphatidylinositol 3-kinase)/AKT and MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal–regulated kinase) pathways, resulting in cell growth arrest and death. Despite the initial clinical efficacy of ALK (anaplastic lymphoma kinase) and EGFR (epidermal growth factor receptor) inhibitors in these cancers, resistance invariably develops, typically within 1 to 2 years. Over the past several years, multiple molecular mechanisms of resistance have been identified, and some common themes have emerged. One is the development of resistance mutations in the drug target that prevent the drug from effectively inhibiting the respective RTK. A second is activation of alternative RTKs that maintain the signaling of key downstream pathways despite sustained inhibition of the original drug target. Indeed, several different RTKs have been implicated in promoting resistance to EGFR and ALK inhibitors in both laboratory studies and patient samples. In this mini-review, we summarize the concepts underlying RTK-mediated resistance, the specific examples known to date, and the challenges of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.”


Bypass Mechanisms of Resistance to Receptor Tyrosine Kinase Inhibition in Lung Cancer

“Receptor tyrosine kinases (RTKs) are activated by somatic genetic alterations in a subset of cancers, and such cancers are often sensitive to specific inhibitors of the activated kinase. Two well-established examples of this paradigm include lung cancers with either EGFR mutations or ALK translocations. In these cancers, inhibition of the corresponding RTK leads to suppression of key downstream signaling pathways, such as the PI3K (phosphatidylinositol 3-kinase)/AKT and MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal–regulated kinase) pathways, resulting in cell growth arrest and death. Despite the initial clinical efficacy of ALK (anaplastic lymphoma kinase) and EGFR (epidermal growth factor receptor) inhibitors in these cancers, resistance invariably develops, typically within 1 to 2 years. Over the past several years, multiple molecular mechanisms of resistance have been identified, and some common themes have emerged. One is the development of resistance mutations in the drug target that prevent the drug from effectively inhibiting the respective RTK. A second is activation of alternative RTKs that maintain the signaling of key downstream pathways despite sustained inhibition of the original drug target. Indeed, several different RTKs have been implicated in promoting resistance to EGFR and ALK inhibitors in both laboratory studies and patient samples. In this mini-review, we summarize the concepts underlying RTK-mediated resistance, the specific examples known to date, and the challenges of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.”