Breast Cancer and CDK-Targeted Therapies

Breast Cancer


Breast cancer (BC) is the leading cause of cancer in women (Global Cancer Observatory, 2020). Although metastatic breast cancer is diagnosed in only 8% of cases at presentation, nearly one third of breast cancer patients with non-metastatic tumors will eventually recur.

In the last few years, the inhibitors of the cell cycle kinases CDK4 and CDK6 (CDK4/6i) have emerged as standard-of-care therapies, together with hormonotherapy (HT), in first and second line in ER-positive HER2-negative advanced BC (Asghar et al., 2015; Finn et al., 2016; ). CDK4 and CDK6 are two serine/threonine kinases, frequently activated in human cancer, involved in cell cycle entry by phosphorylating the retinoblastoma protein (RB1; Malumbres & Barbacid, 2009). Despite their clinical success, their use is still limited due to two major factors: lack of biomarkers and development of acquired resistances. Multiple pathways (e.g. RB1, RAS, AKT, FGFR, cyclin E, etc.) are known to contribute to resistance to CDK4/6i therapy (Li et al., 2918; Wander et al., 2020). Studies assessing efficacy of post-CDK4/6i treatment have been mostly retrospective (André et al., 2019), and few clinical data are available. Thus, how these pathways may modulate response to CDK4/6i in progression of breast or other tumor types is unclear (Alvarez-Fernandez & Malumbres, 2020).

Preclinical data suggested that CDK4/6i may also be active in HER2-positive cancer (Ciruelos et al., 2020). Preliminary clinical data from CDK4/6i plus trastuzumab in HER2+ or in combination with fulvestrant in HER2+ ER+ advanced disease are promising (PATRICIA 1; MONARCH HER). An interesting population of BC is characterized by deficiency in homologous recombination (HR) DNA repair, either from BRCA1/2 mutations (20% of TNBC: 12% germline and 8% somatic) or the “BRCAness” condition, including alterations in PALB2, RAD51, and others (Lord & Ashworth, 2017). These mutations determine a greater sensitivity to platinum chemotherapy as well as to inhibitors of the DNA repair enzyme poly-ADP ribose polymerase 1 (PARPi; Robson et al., 2017), but resistance mechanisms and progression treatment strategies remain unexplored.

Biomarkers and new combinatorial strategies


 

Patients who progress to current therapies (targeting HT + CDK4/6, HER2 or PARP) are therefore in urgent medical need for more prospective, biomarker-driven, clinical trials that test efficacy and safety of new therapeutic strategies.

Despite extensive knowledge of breast cancer biology as well as cell cycle regulation, only estrogen receptor positivity guides CDK4/6i therapy and CCNE1 mRNA expression has been associated with relative resistance (Turner et al., 2018). Yet, the lack of established biomarkers for CDK4/6i efficacy in breast cancer is considered a major limitation (Alvarez-Fernandez & Malumbres, 2020). Liquid biopsy to identifying nucleic acids as well as circulating tumor cells are being implemented in the follow-up and monitoring new therapies response. However, these technologies still suffer of problems in sensitivity and specificity for accurate monitoring. Circulating proteins reflect more precisely the physiological state of cells and tissues. Unfortunately, these biomarker gold mine remains inaccessible due to the lack of proteomics technologies able to explore the deepest region of the plasma proteome.  

  CDK4/6 inhibitors and chemotherapy


Owing to their effect in preventing G1/S transition, CDK4/6 inhibitors are expected to antagonize the effect of classical chemotherapy. It is actually well established that they prevent the cellular effect of DNA-damaging agents or microtubule poisons, which exert their function in S-phase or mitosis, resulting in undesirable antagonistic effects. 

Our recent data suggest, however, that this antagonistic effect can be reversed by alternating treatments in which the DNA-damaging agent or microtubule poison is used first, in the absence of CDK4/6i, and these inhibitors are used later. Interestingly, treatment with CDK4/6i after classical chemotherapy is very efficient to prevent the recovery from these cytotoxic agents (Salvador-Barbero et al., 2020). Mechanistically, these effects are due to a previously-unappreciated requirement for CDK4/6 in the recovery from the chromosomal damage. Upon CDK4/6 inhibition, cancer cells very inefficiently repair this DNA damage and their proliferation is halted both in vitro and in vivo. This is due to a critical role for CDK4/6i in inducing the transcriptional expression of genes required for DNA repair by homologous recombination in a RB1-dependent manner. In addition to taxanes, this synergistic effect was confirmed in the alternating combination of CDK4/6i with DNA-damaging agents such as etoposide, cisplatin, 5-florouracil, etc. as well as anti-mitotic chemicals (kinesin and PLK1 inhibitors).

Importantly, the sequential application of CDK4/6i after microtubule poisons does not significantly increase toxicity as reported in the preclinical model (Salvador-Barbero et al., 2020) and in a recent open-label, phase I clinical trial in which alternating sequential paclitaxel/palbociclib in Rb+ mBC patients was feasible and safe regardless of HR or HER2 expression. Despite the absence of DLT, the presence of G3 neutropenia led to reduce the recommended phase II dose (RP2D) to paclitaxel 80 mg/m2 days +1, +8, +15 and +22 alternating with palbociclib 75 mg (days 2, 3, 4; 9, 10, 11; 16, 17, 18) booth every 28 days. Clinical benefit rate was 55% at the RP2D and benefit was observed across all receptor subtypes (Clark et al., 2019).

Importantly, these data suggest a wide-spectrum of uses of the sequential application of CDK4/6i after radio or chemotherapy in the clinic, and our preliminary data indicates that these findings can be extended to other tumor types in addition to PDAC, including hormone-resistant BC and others. These data also suggest that tumors with alterations that result in resistance to hormonotherapy + CDK4/6i, may still be sensitive to these drugs by the newly-described role of CDK4/6i in the recovery from cellular damage impinged by classical chemotherapy (Salvador-Barbero et al., 2020).

Differential expression of using CDK4/6 inhibitors before (top: antagonism) or after (bottom: synergism) radio or chemotherapy. Source: Alvarez-Fernández & Malumbres, Cancer Cell 2020.

Main Questions


1. Why CDK4/6i have reduced efficacy in tumors others than ER+ breast cancer?

2. Are CDK4 and CDK6 identical? Why CDK6 overexpression seems to drive resistance?

3. Are palbociclib, ribociclib and abemociclib idential? Any distinct therapeutic opportunities?

4. What biomarkers predict sensitivity to CDK4/6 inhibitors?

5. What are the best combinatorial strategies for treating aggressive tumors?

 Further reading


Alvarez-Fernandez M, Malumbres, M. (2020) Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition. Cancer Cell 37, 514-529.

André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor–Positive Advanced Breast Cancer. New England Journal of Medicine 2019; 380:1929–40. .

Asghar, U., Witkiewicz, A. K., Turner, N. C., and Knudsen, E. S. (2015). The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 14, 130-146.

Ciruelos E, Villagrasa P, Pascual T, Oliveira M, Pernas S, Paré L, Escrivá-de-Romaní S, Manso L, Adamo B, Martínez E, Cortés J, Vazquez S, Perelló A, Garau I, Melé M, Martínez N, Montaño A, Bermejo B, Morales S, Echarri MJ, Vega E, González-Farré B, Martínez D, Galván P, Canes J, Nuciforo P, Gonzalez X, Prat A. (2020) Palbociclib and trastuzumab in HER2-positive advanced breast cancer: Results for the phase II SOLTI 1301 PATRICIA trial. Clin Cancer Res 26, 5820–5829.

Clark, A.S. et al. (2019). Combination Paclitaxel and Palbociclib: Results of a Phase I Trial in Advanced Breast Cancer. Clinical Cancer Research 25, 2072-2079.

Finn RS, Martin M, Rugo HS, Jones S, Im S-A, Gelmon K, et al. Palbociclib and Letrozole in Advanced Breast Cancer. New England Journal of Medicine 2016; 375:1925–36. .

Global Cancer Observatory n.d.  (accessed June 5, 2020).

Li Z, Razavi P, Li Q, Toy W, Liu B, Ping C, Hsieh W, Sanchez-Vega F, Brown DN, Da Cruz Paula AF, Morris L, Selenica P, Eichenberger E, Shen R, Schultz N, Rosen N, Scaltriti M, Brogi E, Baselga J, Reis-Filho JS, Chandarlapaty S. (2018) Loss of the FAT1 Tumor Suppressor Promotes Resistance to CDK4/6 Inhibitors via the Hippo Pathway. Cancer Cell 34, 893-905.

Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science 2017;355:1152–8. .

Malumbres, M. (2016) CDK4/6 Inhibitors resTORe Therapeutic Sensitivity in HER²⁺ Breast Cancer. Cancer Cell 29, 243-244.

Malumbres, M., and Barbacid, M. (2001). To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1, 222-231.

Salvador-Barbero B, Álvarez-Fernández M, Zapatero-Solana E, El Bakkali A, Menéndez MDC, López-Casas PP, Di Domenico T, Xie T, VanArsdale T, Shields DJ, Hidalgo M, Malumbres M. (2020) CDK4/6 Inhibitors Impair Recovery from Cytotoxic Chemotherapy in Pancreatic Adenocarcinoma. Cancer Cell 37, 340-353.

Turner NC, Liu Y, Zhu Z, Loi S, Colleoni M, Loibl S, DeMichele A, Harbeck N, André F, Bayar MA, Michiels S, Zhang Z, Giorgetti C, Arnedos M, Huang Bartlett C, Cristofanilli M. (2019) Cyclin E1 Expression and Palbociclib Efficacy in Previously Treated Hormone Receptor-Positive Metastatic Breast Cancer. J Clin Oncol. 37, 1169-1178.

Wander SA, Cohen O, Gong X, Johnson GN, Buendia-Buendia JE, Lloyd MR, Kim D, Luo F, Mao P, Helvie K, Kowalski KJ, Nayar U, Waks AG, Parsons SH, Martinez R, Litchfield LM, Ye XS, Yu C, Jansen VM, Stille JR, Smith PS, Oakley GJ, Chu QS, Batist G, Hughes ME, Kremer JD, Garraway LA, Winer EP, Tolaney SM, Lin NU, Buchanan SG, Wagle N. (2020) The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor-Positive Metastatic Breast Cancer. Cancer Discov 10, 1174-1193.

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