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Mechanisms of Resistance to PI3K and AKT Inhibitors

  • Chapter
  • First Online:
Resistance to Anti-Cancer Therapeutics Targeting Receptor Tyrosine Kinases and Downstream Pathways

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((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.

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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

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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.

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No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA

    Pau Castel

  2. Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Maurizio Scaltriti

  3. Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Maurizio Scaltriti

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  1. Pau Castel
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Correspondence to Maurizio Scaltriti .

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  1. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    Yosef Yarden

  2. Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheeva, Israel

    Moshe Elkabets

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Castel, P., Scaltriti, M. (2018). Mechanisms of Resistance to PI3K and AKT Inhibitors. In: Yarden, Y., Elkabets, M. (eds) Resistance to Anti-Cancer Therapeutics Targeting Receptor Tyrosine Kinases and Downstream Pathways. Resistance to Targeted Anti-Cancer Therapeutics, vol 15. Springer, Cham. https://doi.org/10.1007/978-3-319-67932-7_6

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