The exceptional response to a rapamycin analog in this patient and the underlying mechanism likely hinges on the mutations of PTEN and possibly, to a lesser extent, on STK11, which are both regulators of the downstream mTOR pathway, and the former is known to confer sensitivity to rapamycin analogs in vivo. Given that PTEN is a tumor suppressor, loss of heterozygosity (LOH) was queried on a research basis for both loci, but due to low sample purity could not be determined for either PTEN or STK11 (data not shown).
Loss of function of PTEN, a lipid phosphatase, has long posited as being sensitizing to rapamycin due to ensuing hyperactivation of mTORC1.2 In particular, biallelic loss of function of PTEN should be more sensitizing than mutation of a single allele.2
STK11 is also upstream of mTOR, and loss of function alterations of STK11 also hyperactivate mTORC1, albeit through the intermediary of AMPK activity. However, in preclinical models of STK11-driven dysplasia and neoplasia, only some of these entities are rapamycin sensitive, such the polyps of juvenile polyposis and observation in PIN.3 Overall, whether STK11 alteration confers sensitivity to rapamycin analogs remains poorly understood.
A significant limitation in this study is the inability to identify whether PTEN is under LOH, which would offer a compelling explanation for the efficacy of temsirolimus. The specimen purity did not permit LOH assessment, and no additional specimens were available including original sample (data not shown). Future investigation, whether on the basis of an exceptional responder to rapamycin analog like the patient here or in the context of clinical investigation where the therapeutic hypothesis is a similar question, should incorporate genomic assessment of both alleles of PTEN to help further explain the mechanism of the effect seen here. Studies of both temsirolimus and everolimus in unselected prostate cancer populations did not show an effect, but the latter trended toward some efficacy in a population with PTEN alteration.4,5
One aspect of note is the relatively high tumor mutational burden observed with high PD-L1 staining, but lack of durable response to checkpoint inhibitor. This failure increases the impact of observing a prolonged response to genomically matched targeted therapy for this patient.
In conclusion, the exceptional response observed here suggests that further assessment and investigation is warranted for PTEN status in NSCLC lacking known oncogenic drivers.
The authors apologize to all the investigators whose work cannot be cited here due to limitations of format. Written informed consent was provided by the patient to have the case details published.
ABS, LAA, VAM, PJS, and SMA are employees of and have equity interest in Foundation Medicine Inc. The authors report no other conflicts of interest in this work.
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.
2. Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A. 2001;98(18):10314–10319.
3. Zhou W, Marcus AI, Vertino PM. Dysregulation of mTOR activity through LKB1 inactivation. Chin J Cancer. 2013;32(8):427–433.
4. Kruczek K, Ratterman M, Tolzien K, Sulo S, Lestingi TM, Nabhan C. A phase II study evaluating the toxicity and efficacy of single-agent temsirolimus in chemotherapy-naïve castration-resistant prostate cancer. Br J Cancer. 2013;109(7):1711–1716.
5. Templeton AJ, Dutoit V, Cathomas R, et al. Phase 2 trial of single-agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08). Eur Urol. 2013;64(1):150–158.
Source: Lung Cancer: Targets and Therapy
Originally published May 18, 2018.