Technology

PI3K alpha/mTOR and Cancer

PI3K signaling is one of the most commonly dysregulated pathways in tumor cells; dysregulation can occur by multiple mechanisms including mutational activation or amplification of PI3K, deletion or inactivation of PTEN, and hyperactivation of upstream activators such as RAS and RTKs. There are 4 isoforms of the class I PI3K catalytic domain – PI3K alpha, beta, gamma, and delta. Although all 4 isoforms can promote oncogenic transformation in cultured cells, only PI3K alpha is found to be frequently mutated in human tumors; moreover, PI3K alpha appears to be the dominant isoform involved in RTK signaling. Therefore, PI3K inhibitors may have therapeutic utility in the treatment of cancer, and inhibition of PI3K alpha in particular may be useful for treatment of patients whose tumors harbor PI3K alpha mutations.

The mTOR protein kinase is another key regulator of cellular growth and proliferation, integrating signals from the PI3K pathway with cellular responses to nutrients, energy levels, and oxygen levels. Two distinct mTOR signaling complexes have been identified: mTORC1 (mTOR:RAPTOR) and mTORC2 (mTOR:RICTOR). The mTORC1 complex regulates both ribosomal biogenesis and protein translation, whereas mTORC2 is an activator of AKT, one of the principal effectors of PI3K. Inhibition of both mTORC1 and mTORC2 turns off a feedback loop that upregulates PI3K when only mTORC1 is inhibited. As with PI3K, dysregulation of signaling both upstream and downstream of mTOR is frequently found in cancer and other diseases.

Inhibiting both PI3K alpha and mTOR has been shown to be more effective than inhibiting either target alone in pre-clinical tumor models.

PI3K delta and Cancer

The PI3K delta isoform is overexpressed in B-cell leukemias and lymphomas and plays a key role in cancer cell proliferation and survival. Inhibition of PI3K delta has been clinically validated with a PI3K delta selective inhibitor with responses shown in relapsed or refractory CLL, indolent NHL, and MCL patients.

PI3K delta and Inflammation

PI3K delta is exclusively expressed in leukocytes and is associated with signaling by receptor tyrosine kinases and other cell surface receptors. PI3K delta has been implicated in various autoimmune, inflammatory, and respiratory diseases, including rheumatoid arthritis, allergy, asthma, chronic obstructive pulmonary disease and systemic lupus erythematosus. Hence, selective inhibitors of PI3K delta may have utility in treatment of these and other pathologies of the immune system.