Extended Data Fig. 4: Role of insulin receptor inhibition in the observed changes in tumour response.

a, Western blot of cell lysates from K8484 cells used to generate xenografts in Fig. 4a after 36 treatments with doxycycline to induce the shRenilla and shIR hairpins as indicated. Similar results were observed in two independent experiments. b, Tumour volumes of individual mice allografted with KPC-K8484 tumours as measured by calipers over time. n = 4, 5, 4, 4, 5, 5 and 5 for vehicle, BKM120, BKM120 + ketogenic diet, BKM120 + OSI-906, OSI-906, OSI-906 + ketogenic diet, and ketogenic diet, respectively. c, Survival curves of mice in b. d, e, Mean ± s.d. blood glucose (d) and c-peptide (e) from these mice 240 min after respective treatments. Two of the glucose measurements in the OSI-906 and BKM120 were beyond the range of the detector (>600 mg dl^–1). f, Masses of individual mice over the course of treatment. As has been previously published, mice lose 10–20% of their mass upon initiation of a ketogenic diet²⁹. g, Similar to the data for the tumours in a, both OSI-906, a INSR/IGFR inhibitor, and GDC-0032 showed greater anti-tumour efficacy in PIK3CA + MYC mutant mouse breast tumour allografts, ES-278, grown in wild-type c57/bl6 mice fed a ketogenic diet. n = 5 tumours per arm. Points depict mean ± s.d. tumour volume. h, Mean ± s.d. tumour volumes of wild-type c57/bl6 mice bearing KPC allografted tumours as measured by calipers over time. Mice were treated as indicated with combinations of BYL-719, the ketogenic diet, or insulin as in Fig. 4b. Mice in the ketogenic + BYL719 + insulin cohort lost >20% of their body mass over the 1 week of treatment so the experiment was terminated at day 7. n = 6, 4, 4, 6, 6 for vehicle, BYL-719, ketogenic diet, BYL-719 + ketogenic diet, and BYL-719 + ketogenic diet + insulin, respectively.

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