Abstract CN03-04: PI3K pathway inhibitors: How deep should we go?
Authors: Dienstmann Rodrigo , Rodon Jordi , Saura Cristina , Macarulla Teresa , Perez Jose Manuel , Alsina Maria , Serra Violeta , Felip Enriqueta , Tabernero Josep 
Published: June 2012

Abstract
PI3K pathway activation is commonly observed in human cancer and is critical for tumor progression and resistance to other antineoplastic drugs, both cytotoxic chemotherapy and targeted agents. Several molecular aberrations affecting key components of this pathway have been described, including genetic mutations and amplifications (PIK3CA, AKT) and loss of function of negative regulators (PTEN). Rapalogs were the first inhibitors of downstream effectors of the PI3K pathway to enter the clinic, although with limited antitumor activity. Preclinical studies show that inhibition of mTOR relieves feedback inhibition of receptor tyrosine kinases (RTK), leading to subsequent PI3K/AKT activation. Second generation PI3K pathway inhibitors are still in early phases of clinical development and include: (a) pure pan-PI3K inhibitors; (b) dual PI3K/mTOR inhibitors; (c) AKT inhibitors; (d) mTOR complex 1 and 2 inhibitors; and (d) isoform-specific PI3K inhibitors. Partial responses and prolonged disease stabilization have been reported in multiple tumor types, such as breast, gynecological, prostate, lung, mesotheliomas, sarcomas and lymphomas, although in a lower than expected rate. Pharmacodynamic (PD) studies showed reduction of activation of key pathway readouts both in tumor and surrogate tissues, significant decline in proliferation markers and reduction of glucose avidity on FDG-PET scans, confirming that the targets are being hit. Clinical benefit has not been restricted to patients whose tumor harbor PI3K pathway activation and the PD markers have not shown a clear predictive value. Importantly, the antitumor activity of isoform-specific PI3K inhibitors in PIK3CA mutants is still unknown. Nevertheless, it is now clear that PI3K pathway inhibition increases the activity of MEK/ERK signaling as a result of negative feedback and compensatory RTK stimulation, confirming the adaptive capabilities of oncogenic networks. Therefore, the next generation of trials with PI3K pathway inhibitors should focus in combination strategies, including other targeted therapies, such as BRAF, MEK, EGFR and HER2 inhibitors. For a clear definition of the future role of PI3K pathway inhibitors in the clinic, additional PD studies in these combination trials are of paramount importance. In the case of lack of clinical activity, if the pathway is not effectively inhibited, investigators should go for improved dosing and schedules, provided that toxicity is acceptable. On the other hand, if lack of clinical activity is seen despite effective pathway inhibition, a greater understanding of tumor biology is needed. Results of these studies are eagerly anticipated.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr CN03-04.