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The cell's 'grow and survive' circuit. Growth signals from the surface switch on PI3K, which switches on AKT, which switches on mTOR, which builds proteins and blocks self-destruction.
Receptor tyrosine kinases (HER2, EGFR, IGF1R) activate PI3K (p110α, encoded by PIK3CA), producing PIP3, which recruits AKT. PTEN reverses this step and is a tumour suppressor. AKT phosphorylates many targets including TSC2, releasing mTORC1 to drive protein synthesis, and inhibits FOXO and BAD. The most frequently altered pathway in cancer: PIK3CA mutation (~40% HR+ breast, endometrial, head and neck), PTEN loss (prostate, endometrial, glioblastoma), AKT1 E17K. Drugs: alpelisib, inavolisib (PI3Kα), capivasertib (AKT), everolimus (mTOR), gedatolisib (PI3K/mTOR). Feedback: mTOR inhibition releases AKT, so combinations and endocrine partners are needed.
Think of a factory: the receptor is the order desk, PI3K and AKT are the managers relaying the order, PTEN is the accountant cancelling orders, and mTOR is the assembly line. Cancer forges orders (PIK3CA mutation) or fires the accountant (PTEN loss).
The latest in a line of negative targeted-therapy trials in triple-negative disease (EGFR, VEGF, iniparib, now AKT): a modest delay in progression that did not translate into survival, in the same year that an antibody-drug conjugate did. It is why the roadmap treats pathway-targeted small molecules as the road not taken.
It is the prospective test of the PI3K and androgen receptor feedback hypothesis in men, and it shows both halves of the answer: the biomarker-selected population benefits, and the benefit is small enough that the toxicity has to be weighed honestly.
PAKT gives the trial-based prevalence of PI3K-pathway alteration in first-line metastatic TNBC (one in five) and the strongest signal for AKT inhibition in that subgroup; the phase 3 CAPItello-290 did not confirm it.
It splits the alterations into two groups with different practical meanings. The repair defects are present at diagnosis at close to their castration-resistant prevalence, so testing early is worthwhile; AR, TP53 and RB1 changes accumulate later, so a diagnostic sample does not answer questions about the disease in front of you at relapse.
This is the sourced bridge between expression subtype and mutation: it tells a clinician that a LAR tumour is the one to sequence for PIK3CA and AKT1, and that immunomodulatory biology is a favourable prognostic group before any immunotherapy.
It is the study that justified using plasma instead of a bone biopsy in this disease, with the honest caveat attached: the concordance holds only above a tumour fraction threshold, and below it the test is uninformative rather than negative.
LOTUS and PAKT together made the PI3K/AKT/PTEN-altered subgroup the target population for AKT inhibitors in TNBC; the phase 3 IPATunity130 later failed to confirm it, which is why no AKT inhibitor is approved here.
It validates a clinical definition against a molecular one, which is unusual and useful: a man whose disease behaves like small cell carcinoma can be treated as such even when his biopsy does not look like it, because the underlying genotype is the same.
Shares Salmonella manipulation of host signaling pathways provokes cellular transformation associated with gallbladder carcinoma, Phosphorylation, GRB7, Salmonella Typhi carriage and gallbladder cancer.
Shares Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate, LOTUS, Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial.
Shares Comprehensive molecular portraits of human breast tumours, MicroRNAs in cancer, Combined tumour suppressor defects characterise clinically defined aggressive variant prostate cancers, Genomics of lethal prostate cancer at diagnosis and castration resistance.
Shares Salmonella manipulation of host signaling pathways provokes cellular transformation associated with gallbladder carcinoma, Salmonella Typhi carriage and gallbladder cancer, Comprehensive molecular portraits of human breast tumours, Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis.
Shares CAPItello-281, LOTUS, IPATunity130, PAKT.
Shares Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate, Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial, IPATential150: ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer.
Shares PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate, IPATential150: ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer, Reciprocal feedback regulation of PI3K and androgen receptor signalling in PTEN-deficient prostate cancer, Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.
Shares Comprehensive molecular portraits of human breast tumours, Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis, Combined tumour suppressor defects characterise clinically defined aggressive variant prostate cancers, Concordance of circulating tumour DNA and matched metastatic tissue biopsy in prostate cancer.