Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation

doi:10.1186/s13058-019-1154-8

Clinical Trial

. 2019 Jul 5;21(1):78.

doi: 10.1186/s13058-019-1154-8.

Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation

Yan Xing¹, Nancy U Lin², Matthew A Maurer^{3

4}, Huiqin Chen⁵, Armeen Mahvash⁶, Aysegul Sahin⁷, Argun Akcakanat¹, Yisheng Li⁵, Vandana Abramson⁸, Jennifer Litton⁹, Mariana Chavez-MacGregor^{9

10}, Vicente Valero⁹, Sarina A Piha-Paul¹, David Hong¹, Kim-Anh Do⁵, Emily Tarco¹, Dianna Riall¹¹, Agda Karina Eterovic¹², Gerburg M Wulf¹³, Lewis C Cantley¹⁴, Gordon B Mills¹², L Austin Doyle¹⁵, Eric Winer², Gabriel N Hortobagyi⁹, Ana Maria Gonzalez-Angulo⁹, Funda Meric-Bernstam^{16

17

18}

Affiliations

¹ Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
² Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
³ Columbia University, New York, NY, 10027, USA.
⁴ Present address: Bristol-Myers Squibb, Princeton, NJ, 08540, USA.
⁵ Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁶ Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁷ Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁸ Vanderbilt University, Nashville, TN, 37232, USA.
⁹ Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹⁰ Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹¹ IND Office, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹² Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹³ Department of Medicine, Beth Israel Deaconess Medical Center and Dana Farber Harvard Cancer Center, Boston, MA, 02215, USA.
¹⁴ Cornell University, Ithaca, NY, 14850, USA.
¹⁵ National Cancer Institute, Bethesda, MD, 20892, USA.
¹⁶ Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. fmeric@mdanderson.org.
¹⁷ The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. fmeric@mdanderson.org.
¹⁸ Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Boulevard, Unit 455, Houston, TX, 77030, USA. fmeric@mdanderson.org.

PMID: 31277699
PMCID: PMC6612080
DOI: 10.1186/s13058-019-1154-8

Clinical Trial

Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation

Yan Xing et al. Breast Cancer Res. 2019.

. 2019 Jul 5;21(1):78.

doi: 10.1186/s13058-019-1154-8.

Authors

Affiliations

¹ Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
² Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
³ Columbia University, New York, NY, 10027, USA.
⁴ Present address: Bristol-Myers Squibb, Princeton, NJ, 08540, USA.
⁵ Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁶ Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁷ Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁸ Vanderbilt University, Nashville, TN, 37232, USA.
⁹ Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹⁰ Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹¹ IND Office, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹² Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
¹³ Department of Medicine, Beth Israel Deaconess Medical Center and Dana Farber Harvard Cancer Center, Boston, MA, 02215, USA.
¹⁴ Cornell University, Ithaca, NY, 14850, USA.
¹⁵ National Cancer Institute, Bethesda, MD, 20892, USA.
¹⁶ Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. fmeric@mdanderson.org.
¹⁷ The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. fmeric@mdanderson.org.
¹⁸ Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Boulevard, Unit 455, Houston, TX, 77030, USA. fmeric@mdanderson.org.

PMID: 31277699
PMCID: PMC6612080
DOI: 10.1186/s13058-019-1154-8

Abstract

Background: The PI3K/AKT pathway is activated through PIK3CA or AKT1 mutations and PTEN loss in breast cancer. We conducted a phase II trial with an allosteric AKT inhibitor MK-2206 in patients with advanced breast cancer who had tumors with PIK3CA/AKT1 mutations and/or PTEN loss/mutation.

Methods: The primary endpoint was objective response rate (ORR). Secondary endpoints were 6-month progression-free survival (6 m PFS), predictive and pharmacodynamic markers, safety, and tolerability. Patients had pre-treatment and on-treatment biopsies as well as collection of peripheral blood mononuclear cells (PBMC) and platelet-rich plasma (PRP). Next-generation sequencing, immunohistochemistry, and reverse phase protein arrays (RPPA) were performed.

Results: Twenty-seven patients received MK-2206. Eighteen patients were enrolled into the PIK3CA/AKT1 mutation arm (cohort A): 13 had PIK3CA mutations, four had AKT1 mutations, and one had a PIK3CA mutation as well as PTEN loss. ORR and 6 m PFS were both 5.6% (1/18), with one patient with HR+ breast cancer and a PIK3CA E542K mutation experiencing a partial response (on treatment for 36 weeks). Nine patients were enrolled on the PTEN loss/mutation arm (cohort B). ORR was 0% and 6 m PFS was 11% (1/9), observed in a patient with triple-negative breast cancer and PTEN loss. The study was stopped early due to futility. The most common adverse events were fatigue (48%) and rash (44%). On pre-treatment biopsy, PIK3CA and AKT1 mutation status was concordant with archival tissue testing. However, two patients with PTEN loss based on archival testing had PTEN expression on the pre-treatment biopsy. MK-2206 treatment was associated with a significant decline in pAKT S473 and pAKT T308 and PI3K activation score in PBMC and PRPs, but not in tumor biopsies. By IHC, there was no significant decrease in median pAKT S473 or Ki-67 staining, but a drop was observed in both responders.

Conclusions: MK-2206 monotherapy had limited clinical activity in advanced breast cancer patients selected for PIK3CA/AKT1 or PTEN mutations or PTEN loss. This may, in part, be due to inadequate target inhibition at tolerable doses in heavily pre-treated patients with pathway activation, as well as tumor heterogeneity and evolution in markers such as PTEN conferring challenges in patient selection.

Trial registration: ClinicalTrials.gov, NCT01277757 . Registered 13 January 2011.

Keywords: AKT signaling; Biomarkers; Genomics; PIK3CA mutation; PTEN loss.

PubMed Disclaimer

Conflict of interest statement

V. Abramson, A. Akcakanat, H. Chen, K-A Do, L.A. Doyle, A.K Eterovic, A.M. Gonzalez-Angulo, G.M. Wulf, L. Yisheng, A. Mahvash, D. Riall, A. Sahin, E. Tarco, V. Valero, Y. Xing have nothing to disclose.

L. C. Cantley reports grants from NCI, Stand Up To Cancer/AACR, Breast Cancer Research Foundation, and the Jon and Mindy Gray Foundation during the conduct of this study. He has a patent: improving responses to cancer drugs by dietary and pharmaceutical interventions that lower serum insulin pending. He is a founder and member of the SAB of Agios Pharmaceuticals and of Petra Pharmaceuticals. These companies are developing novel therapies for cancer. His laboratory also receives some financial support from Petra Pharmaceuticals.

M. Chavez-MacGregor reports grant from Novartis and consulting fees from Roche and Pfizer.

D. Hong reports grants from Merck, Daichii-Sanko, Eisai, Adaptimmune, Abbvie, Astra-Zeneca, BMS, Genmab, infinity, Kite, Kyowa, Medimmune, Molecular Template, Novartis, and Takeda, and personal fees from Mima, LOXO, Bayer, Baxter, Guidepoint Global, Oncoresponse, Takeda, Janssen, and Molecular Match.

R. Hortobagyi reports grants from Merck.

N.U. Lin reports grants from Pfizer, Genentech/Roche, Kadmon, Novartis, and Array Biopharma, and personal fees from Genentech, Shionogi Inc., Seattle Genetics, and Daichii.

J. Litton reports grants from Pfizer, Astra Zeneca, Genentech, EMD Serono, and GSK.

M.A. Mauer is a fulltime employee of Bristol Myers-Squibb. His work at BMS has no direct relationship to the work in this study.

F. Meric-Bernstam reports receiving commercial research grants from Novartis, AstraZeneca, Calithera, Aileron, Bayer, Jounce, CytoMx, eFFECTOR, Zymeworks, PUMA Biotechnology, Curis, Millennium, Daiichi Sankyo, Abbvie, Guardant Health, Takeda, and GlaxoSmithKline as well as grants and travel-related fees from Taiho, Genentech, Debiopharm Group, and Pfizer. She also served as a consultant to Pieris, Dialectica, Sumitomo Dainippon, Samsung Bioepis, Aduro, OrigiMed, Xencor, and Jackson Laboratory, and advisor to Inflection Biosciences, GRAIL, Darwin Health, Clearlight Diagnostics, Spectrum, and Mersana.

G.B. Mills reports grants from Adelson Medical Research Foundation, AstraZeneca, Breast Cancer Research Foundation, Immunomet, Ionis, KarusTherapeutics, Komen Research Foundation,Nanostring, Ovarian Cancer Research Foundation, Pfizer, Prospect Creek Foundation, and Takeda/Millennium Pharmaceuticals; personal fees from AstraZeneca, Catena Pharmaceuticals, Critical Outcome Technologies, ImmunoMET, Ionis, SignalchemLifesciences, Symphogen, Takeda/Millennium Pharmaceuticals, and Tarveda; stock/financial interest in Catena Pharmaceuticals, ImmunoMet, SignalChem, Spindle Top Ventures, and Tarveda; and licensed technology in HRD assay to Myriad Genetics.

S.A. Piha-Paul reports grants from Merck Sharp & Dohme Corp, Genmab, Taiho Oncology, Medimume, LLC, BioMarin Pharmaceutical, Inc., Novartis Pharmaceuticals, Principia Biopharma, Inc., Abbvie, Merck, Pieris Pharmaceuticals, Inc., Puma Biotechnology, Inc., GlaxoSmithKline, Helix BioPharma Corp, Curis, Tesaro, and Medivation.

E. Winer reports personal fees from Genentech, Leap, InfiniteMD, Lilly, Carrick Therapeutics, GSK, and Verastem.

Figures

**Fig. 1**
Individual swimmer plots for each patient in the overall study population. Depicting progression-free survival (PFS) for PTEN cohort (blue), and PFS for PIK3CA/AKT cohort (red). Patients who discontinued MK-2206 due to toxicity are depicted with a (#), while patients who discontinued MK-2206 due to patient choice are depicted with a (*). Two patients who were enrolled on the PTEN loss cohort had PTEN expressions on the pre-treatment biopsy sample are depicted with a (&). A patient who had both PTEN loss and *PIK3CA* mutation is depicted with a (^). One patient who had partial response starting at 12 weeks (▲)

**Fig. 2**
The effect of MK-2206 on signaling in PBMC and PRP samples. Differences between baseline and post-treatment expression of pAKT-T308, pAKT-S473, pS6 S235/236 and pS6 S240/244 with two-sided t test. P < .05 was considered statistically significant. a Upper panel—platelets: group 1: early and C1D1: post-treatment, early and C1D2 for 15 patients who have early samples available. Group 2: C1D1:pre-treatment and C1D1: post-treatment, C1D1:pre-treatment and C1D2 for 13 patients who have C1D1:pre-treatment available. Lower panel—PBMC: group 1: early and C1D1:post-treatment, Early and C1D2 for 15 patients who have early samples available Group 2: C1D1:pre-treatment and C1D1:post-treatment, C1D1:pre-treatment and C1D2 for 13 patients who have C1D1:pre-treatment available. b Tumor

**Fig. 3**
Expression of PI3K/AKT/mTOR signaling pathway markers in paired baseline and on-treatment samples. a IRS score for pAKT S473, pS6 S235/236, pS6 S240/244, and Ki-67 in paired baseline and on-treatment samples. b Expression of PI3K/AKT/mTOR signaling pathway markers in the two patients who demonstrated clinical benefit. Upper panel, patient with partial response in PIK3CA cohort; bottom panel, patient with stable disease in PTEN cohort

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References

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1. Miller TW, Perez-Torres M, Narasanna A, Guix M, Stal O, Perez-Tenorio G, Gonzalez-Angulo AM, Hennessy BT, Mills GB, Kennedy JP, et al. Loss of phosphatase and tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res. 2009;69(10):4192–4201. doi: 10.1158/0008-5472.CAN-09-0042. - DOI - PMC - PubMed
1. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6(2):117–127. doi: 10.1016/j.ccr.2004.06.022. - DOI - PubMed
1. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12(4):395–402. doi: 10.1016/j.ccr.2007.08.030. - DOI - PubMed
1. Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, Baird RD, Delgado L, Taylor A, Lupinacci L, et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol. 2011;29(35):4688–4695. doi: 10.1200/JCO.2011.35.5263. - DOI - PubMed

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[1] Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She QB, Maurer M, Koujak S, Ferrando AA, Malmstrom P, Memeo L, et al. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci U S A. 2007;104(18):7564–7569. doi: 10.1073/pnas.0702507104. - DOI - PMC - PubMed

[2] Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She QB, Maurer M, Koujak S, Ferrando AA, Malmstrom P, Memeo L, et al. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci U S A. 2007;104(18):7564–7569. doi: 10.1073/pnas.0702507104. - DOI - PMC - PubMed

[3] Miller TW, Perez-Torres M, Narasanna A, Guix M, Stal O, Perez-Tenorio G, Gonzalez-Angulo AM, Hennessy BT, Mills GB, Kennedy JP, et al. Loss of phosphatase and tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res. 2009;69(10):4192–4201. doi: 10.1158/0008-5472.CAN-09-0042. - DOI - PMC - PubMed

[4] Miller TW, Perez-Torres M, Narasanna A, Guix M, Stal O, Perez-Tenorio G, Gonzalez-Angulo AM, Hennessy BT, Mills GB, Kennedy JP, et al. Loss of phosphatase and tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res. 2009;69(10):4192–4201. doi: 10.1158/0008-5472.CAN-09-0042. - DOI - PMC - PubMed

[5] Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6(2):117–127. doi: 10.1016/j.ccr.2004.06.022. - DOI - PubMed

[6] Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6(2):117–127. doi: 10.1016/j.ccr.2004.06.022. - DOI - PubMed

[7] Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12(4):395–402. doi: 10.1016/j.ccr.2007.08.030. - DOI - PubMed

[8] Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12(4):395–402. doi: 10.1016/j.ccr.2007.08.030. - DOI - PubMed

[9] Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, Baird RD, Delgado L, Taylor A, Lupinacci L, et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol. 2011;29(35):4688–4695. doi: 10.1200/JCO.2011.35.5263. - DOI - PubMed

[10] Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, Baird RD, Delgado L, Taylor A, Lupinacci L, et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol. 2011;29(35):4688–4695. doi: 10.1200/JCO.2011.35.5263. - DOI - PubMed

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Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation

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Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation

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