Shimony, S., Stahl, M. & Stone, R. M. Acute myeloid leukemia: 2023 update on diagnosis, risk-stratification, and management. Am. J. Hematol. 98, 502–526 (2023).

Article  PubMed  Google Scholar 

Appelbaum, F. R. et al. Age and acute myeloid leukemia. Blood 107, 3481–3485 (2006).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bhansali, R. S., Pratz, K. W. & Lai, C. Recent advances in targeted therapies in acute myeloid leukemia. J. Hematol. Oncol. 16, 29 (2023).

Article  PubMed  PubMed Central  Google Scholar 

DiNardo, C. D. et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 133, 7–17 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

DiNardo, C. D. et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N. Engl. J. Med. 383, 617–629 (2020).

Article  CAS  PubMed  Google Scholar 

Tsherniak, A. et al. Defining a cancer dependency map. Cell 170, 564–576 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Burger, J. A. Treatment of chronic lymphocytic leukemia. N. Engl. J. Med. 383, 460–473 (2020).

Article  CAS  PubMed  Google Scholar 

Jordan, V. C. & O’Malley, B. W. Selective estrogen-receptor modulators and antihormonal resistance in breast cancer. J. Clin. Oncol. 25, 5815–5824 (2007).

Article  CAS  PubMed  Google Scholar 

Watson, P. A., Arora, V. K. & Sawyers, C. L. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat. Rev. Cancer 15, 701–711 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yu, A. L. et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N. Engl. J. Med. 363, 1324–1334 (2010).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Burger, J. A. et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia 34, 787–798 (2020).

Article  CAS  PubMed  Google Scholar 

Millis, S. Z., Ikeda, S., Reddy, S., Gatalica, Z. & Kurzrock, R. Landscape of phosphatidylinositol-3-kinase pathway alterations across 19 784 diverse solid tumors. JAMA Oncol. 2, 1565–1573 (2016).

Article  PubMed  Google Scholar 

Hirai, H. et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol. Cancer Ther. 9, 1956–1967 (2010).

Article  CAS  PubMed  Google Scholar 

Maira, S. M. et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol. Cancer Ther. 11, 317–328 (2012).

Article  CAS  PubMed  Google Scholar 

Maira, S. M. et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol. Cancer Ther. 7, 1851–1863 (2008).

Article  CAS  PubMed  Google Scholar 

Di Leo, A. et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 19, 87–100 (2018).

Article  PubMed  Google Scholar 

Hopkins, B. D. et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560, 499–503 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Krop, I. E. et al. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 17, 811–821 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Furman, R. R. et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 370, 997–1007 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

De Henau, O. et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature 539, 443–447 (2016).

Article  PubMed  PubMed Central  Google Scholar 

Foubert, P., Kaneda, M. M. & Varner, J. A. PI3Kγ activates integrin α4 and promotes immune suppressive myeloid cell polarization during tumor progression. Cancer Immunol. Res. 5, 957–968 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schmid, M. C. et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19, 715–727 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kaneda, M. M. et al. PI3Kγ is a molecular switch that controls immune suppression. Nature 539, 437–442 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hong, D. S. et al. Eganelisib, a first-in-class PI3Kγ inhibitor, in patients with advanced solid tumors: results of the phase 1/1b MARIO-1 trial. Clin. Cancer Res. 29, 2210–2219 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gu, H. et al. PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway. Blood 143, 1965–1979 (2024).

Article  CAS  PubMed  Google Scholar 

Tyner, J. W. et al. Functional genomic landscape of acute myeloid leukaemia. Nature 562, 526–531 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

van Galen, P. et al. Single-cell RNA-seq reveals AML hierarchies relevant to disease progression and immunity. Cell 176, 1265–1281 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Ng, S. W. et al. A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature 540, 433–437 (2016).

Article  CAS  PubMed  Google Scholar 

Cancer Genome Atlas Research, N. et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074, (2013).

Article  Google Scholar 

Shymanets, A. et al. p87 and p101 subunits are distinct regulators determining class IB phosphoinositide 3-kinase (PI3K) specificity. J. Biol. Chem. 288, 31059–31068 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Stephens, L. R. et al. The Gβγ sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101. Cell 89, 105–114 (1997).

Article  CAS  PubMed  Google Scholar 

Horejsi, Z. et al. CK2 phospho-dependent binding of R2TP complex to TEL2 is essential for mTOR and SMG1 stability. Mol. Cell 39, 839–850 (2010).

Article  CAS  PubMed  Google Scholar 

Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science 307, 1098–1101 (2005).

Article  CAS  PubMed  Google Scholar 

Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 296, 1655–1657 (2002).

Article  CAS  PubMed  Google Scholar 

Pham, L. V. et al. Strategic therapeutic targeting to overcome venetoclax resistance in aggressive B-cell lymphomas. Clin. Cancer Res. 24, 3967–3980 (2018).

Article  CAS  PubMed  Google Scholar 

Sathe, A. et al. Parallel PI3K, Akt and mTOR inhibition is required to control feedback loops that limit tumor therapy. PLoS ONE 13, e0190854 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Tavor, S. et al. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice. Cancer Res. 64, 2817–2824 (2004).