Mechanisms of Resistance to PI3K and AKT Inhibitors

Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 15)

Abstract

Hyperactivation of the PI3K pathway is frequent in human cancer. Whether it occurs via overexpression/phosphorylation of upstream receptors that promote the binding and activation of PI3K, or as a consequence of activating alterations of the nodes of the signaling cascade, deregulated PI3K signaling can promote tumor growth and survival. This provided the rationale to develop inhibitors targeting virtually all the components of this pathway. Despite these efforts, however, the responses in the clinic have been anecdotal and short lived for most of these agents.

In the last few years, clinical studies have demonstrated that specific compounds can elicit strong antitumor activity if administered to selected patients. For example, AKT catalytic inhibitors and specific PI3Kα inhibitors have shown promising clinical responses in patients with tumors bearing activating mutations of AKT and PIK3CA, respectively. Nevertheless, the intrinsic or acquired resistance to PI3K/AKT/mTOR inhibitors limits the activity of these agents. The mechanisms that tumor cells adopt to by-pass pharmacological inhibition of PI3K/AKT/mTOR are tissue-dependent and can be the results of either pre-existing conditions that rapidly compensate for the therapeutic pressure or the acquisition of genomic and/or epigenomic changes that confer fitness over time even upon PI3K full blockade. In both cases, combinatorial strategies seem to be necessary to prevent or delay the emergence of drug resistance, and many of these therapeutic options are currently being tested in the clinic.

Keywords

Signaling pathway Drug resistance Targeted therapy Protein kinase 

Abbreviations

AGC

Protein Kinase A, G, And C Kinase Family

AKT

RAC-Alpha Serine/Threonine-Protein Kinase

AMP

Adenosine Monophosphate

AMPK

AMP-Dependent Protein Kinase

ARF

ADP Ribosylation Factors

ATP

Adenosine Triphosphate

BAD

BCL2 Associated Agonist of Cell Death

BCL2

B-Cell Lymphoma 2

BRD4

Bromodomain And Extra Terminal Domain 4

Cdc42

Cell Division Cycle 42

DEPTOR

DEP Domain-Containing Mtor-Interacting Protein

Eif4e

Eukaryotic Translation Initiation Factor 4E

ER

Estrogen Receptor

ERK

Extracellular Signal–Regulated Kinase

FOXA1

Forkhead Box A1

FOXG1

Forkhead Box G1

FOXO

Forkhead Box O

GAP

GTP-Ase Activating Protein

GDP

Guanosine Diphosphate

GTP

Guanosine Triphosphate

H3k4me1/2

Histone 3 Lysine 4 Mono−/Di-Methylated

HER2

Human Epidermal Growth Factor Receptor 2

IGFR1

Insulin-Like Growth Factor 1 Receptor 1

IRS1

Insulin Receptor Substrate 1

KMT2D

Histone-Lysine N-Methyltransferase 2D

LKB1

Liver Kinase B1

MAPK

Mitogen-Activated Protein Kinases

MEK

MAPK/ERK Kinase

MLST8

Mammalian Lethal with SEC13 Protein 8

MYC

V-Myc Avian Myelocytomatosis Viral Oncogene Homolog

P16ink4a

16 kDa Inhibitor of Cyclin-Dependent Kinase Type 4A

P21CIP1

21 kDa CDK-Interacting Protein 1

P27KIP

27 kDa Kinase Inhibitor Protein

PBX1

Pre-B-Cell Leukemia Transcription Factor 1

PDK1

3-Phosphoinositide Dependent Protein Kinase-1

PGC-1

Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1

PIF

PDK1-Interacting Fragment

PIM

Proviral Integration Site for Moloney Murine Leukemia Virus-1

PKC

Protein Kinase C

PRAS40

Proline-Rich Akt Substrate of 40 kDa

PROTOR

Protein Observed with Rictor-1

PTEN

Phosphatase and Tensin Homolog

Rac1

Ras-Related C3 Botulinum Toxin Substrate 1

RAF

Rapidly Accelerated Fibrosarcoma

RAPTOR

Regulatory Associated Protein of MTOR Complex 1

RHEB

Ras Homolog Enriched in Brain

RICTOR

Rapamycin-Insensitive Companion of MTOR

RSK

90 kDa Ribosomal S6 Kinase

SH2

Src Homology 2

SIN1

Stress-Activated Map Kinase-Interacting Protein 1

SMAD

Mothers Against Decapentaplegic Homolog

TSC2

Tuberous Sclerosis Complex Protein 2

VPS15

Vacuolar Protein Sorting 15

VPS34

Vacuolar Protein Sorting 34

Notes

Acknowledgments

We would like to thank the Breast Cancer Research Foundation and the Geoffrey Beene Cancer Research Center. Pau Castel is a Fellow of the Jane Coffin Childs Memorial Fund. We apologize for the impossibility to cite every author who has contributed to this field of inquiry.

Conflict of Interest

No potential conflicts of interest were disclosed.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Helen Diller Family Comprehensive Cancer CenterUniversity of California San FranciscoSan FranciscoUSA
  2. 2.Human Oncology & Pathogenesis Program (HOPP)Memorial Sloan Kettering Cancer CenterNew YorkUSA
  3. 3.Department of PathologyMemorial Sloan Kettering Cancer CenterNew YorkUSA

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